Devices, systems and methods for using and monitoring medical devices

ABSTRACT

Medical devices are provided, comprising a medical device and a sensor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 62/051,855 filed Sep. 17, 2014, andU.S. Provisional Patent Application No. 62/184,820 filed Jun. 25, 2015,which applications are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION Technical Field

The present invention relates generally to medical devices, and morespecifically, to devices and methods for monitoring the placement,efficacy, durability and performance of a wide variety of temporaryand/or permanently implantable medical devices.

BACKGROUND Description of the Related Art

Medical devices and implants have become common-place in modem medicine.Typically, medical devices and implants are manufactured to replace,support, or enhance an anatomical or biological structure. Examples ofmedical devices include cardiovascular implants such as implantablecardioverter defibrillators, pacemakers, stents, stent grafts, bypassgrafts, catheters and heart valves; orthopedic implants such as hip andknee prosthesis; spinal implants and hardware (spinal cages, screws,plates, pins, rods and artificial discs); intrauterine devices;orthopedic hardware used to repair fractures and soft tissue injuries(casts, braces, tensor bandages, plates, screws, pins and plates);cochlear implants; aesthetic implants (breast implants, fillers); dentalimplants: medical polymers; and artificial intraocular eye lenses.

Unfortunately, various complications may arise during insertion of themedical device or implant (whether it is an open surgical procedure or aminimally invasive procedure). For example, a surgeon may wish toconfirm correct anatomical alignment and placement of the implant withinsurrounding tissues and structures. This can however be difficult to doduring the procedure itself, making corrective adjustments difficult.

In addition, a patient may experience a number of complicationspost-procedure. Such complications include neurological symptoms, pain,malfunction (blockage, loosening, etc.) and/or wear of the implant,movement or breakage of the implant, inflammation and/or infection.While some of these problems can be addressed with pharmaceuticalproducts and/or further surgery, they are difficult to predict andprevent; often early identification of complications and side effects isdifficult or impossible.

The present invention discloses novel medical devices and implants whichcan overcome many of the difficulties and limitations found withprevious medical devices and implants, methods for constructing andmonitoring these novel medical devices and implants, and furtherprovides other related advantages.

All of the subject matter discussed in the Background section is notnecessarily prior art and should not be assumed to be prior art merelyas a result of its discussion in the Background section. Along theselines, any recognition of problems in the prior art discussed in theBackground section or associated with such subject matter should not betreated as prior art unless expressly stated to be prior art. Instead,the discussion of any subject matter in the Background section should betreated as part of the inventor's approach to the particular problem,which in and of itself may also be inventive.

SUMMARY

Briefly stated, medical devices and implants (also referred to as‘medical devices’) are provided comprising a medical device along withone or more ISMs (“Implantable Sensor Modules”) which can be utilized tomonitor the integrity and efficaciousness of the medical device.

Representative examples of medical devices and implants include, forexample, cardiovascular devices and implants such as implantablecardioverter defibrillators, pacemakers, stents, stent grafts, bypassgrafts, catheters and heart valves; orthopedic implants such as hip andknee prosthesis; spinal implants and hardware (spinal cages, screws,plates, pins, rods and artificial discs); a wide variety of medicaltubes, cosmetic and/or aesthetic implants (e.g., breast implants,fillers); a wide variety of polymers; intrauterine devices; orthopedichardware (e.g., casts, braces, tensor bandages, external fixationdevices, tensors, slings and supports) and internal hardware (e.g.,K-wires, pins, screws, plates, and intramedullary devices (e.g., rodsand nails)); cochlear implants; dental implants; medical polymers, awide variety of neurological devices; and artificial intraocular eyelenses.

The ISMs may be positioned on the inside of the medical device, withinthe body of the medical device, or on the outer/inner surface (orsurfaces) of the medical device, and/or between the medical device andany device that might be utilized to deliver the implant, as well ascements, sutures and glues that may also be utilized within a surgicalprocedure. Within certain embodiments, the sensors are of the type thatare passive and thus do not require their own power supply.

Within one embodiment of the invention, the ISM is a self-containedmodule having one or more sensors as described herein, a sensorinterface, a processor interface, battery management, and a wirelessinterface. Within preferred embodiments of the invention the ISM will beless than 5, 4, 3, 2, or 1 cubic centimeter in size, and morepreferably, less than 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.9,0.8. 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 cubic centimeters in size.Within various embodiments the ISM can be comprised of a solid outercore, or composed of flexible materials (e.g., a degradable ornon-degradable outer polymeric surface). Within certain embodiments theISM may be relatively square and solid, and yet with in otherembodiments very thin, malleable and lengthy (as compared to its widthand/or height). It can be constructed for a number of differentapplications (e.g., for insertion or implantation into any of themedical devise or implants provided herein).

ISMs can also be utilized in delivery devices which are associated with,or used along with the medical device and implant. Representativeexamples include drills, drill guides, mallets, guidewires, catheters,balloons, trocars, endoscopes, bone tunneling catheters, microsurgicaltools and general surgical tools.

In addition, further components or compositions may be delivered alongwith the medical device and implant which also can have or contain anISM, including for example, fillers such as sutures, glues, collagen,fibrin, growth factors, barriers, hemostats, bone cement and polymerssuch as PMMA.

Within preferred embodiments of the above, the ISM, medical device,medical delivery device and filler are all provided in a sterile form(e.g., ETO sterilized), non-pyrogenic, suitable for use in humans and ina kit containing components suitable for a particular surgery. Withinfurther embodiments one or more of the components may be providedtogether as a kit.

Representative examples of sensors which may be contained within an ISMand which are suitable for use within the present invention includeaccelerometers (acceleration, tilt, vibration, shock and rotationsensors), pressure sensors, contact sensors, position sensors, chemicalsensors, tissue metabolic sensors, mechanical stress sensors, auditorysensors and temperature sensors. Within particularly preferredembodiments the sensor is a wireless sensor, or a sensor connected to awireless microprocessor. Within further embodiments the medical device,delivery device or surgical tool can have more than one type of theabove-noted sensors.

According to various embodiments, sensors can be placed into an ISM atdifferent locations in order to monitor the operation, movement,anatomical location, medical imaging (both of the medical device and thesurrounding tissues), function, physical integrity, wear, performance,potential side effects, medical status of the patient and the medicalstatus of the medical device and its interface with the live tissue ofthe patient. Live, continuous or intermittent, in situ, monitoring ofpatient activity, patient function, medical device activity, medicaldevice function, medical device performance, medical device placement,medical device forces and mechanical stresses, medical device andsurrounding tissue anatomy (imaging), mechanical, functional andphysical integrity of the medical device, and potential local andsystemic side effects is provided. In addition, information is availableon many aspects of the medical device and its interaction with thepatient's own body tissues, including clinically important measurementsnot currently available through physical examination, medical imagingand diagnostic medical studies.

According to one embodiment, the ISM has one or more sensors to provideevaluation data of any motion or movement of the medical device. Motionsensors and accelerometers can be used to accurately determine themovement of the medical device and to determine if there is movementbetween the device and surrounding tissue (e.g., bone, blood vessels,soft tissues, organs). Such evaluation can be utilized to help reducethe incidence of improper placement, alignment and deployment duringsurgical placement, migration/breakage/wear during medical and physicalexamination post-operatively, and malfunction or side effects duringnormal daily activities after the patient returns home.

According to another embodiment, ISMs having contact sensors areprovided between the medical device and implant and the surroundingtissue and/or between articulated components of the device/implantitself (e.g., in the case of orthopedic devices or implants, stentgrafts, overlapping stents, heart valves, etc.). In other embodiments,vibration sensors are provided to detect the vibration between themedical device and/or the surrounding tissue. In other embodiments, ISMshaving strain gauges are provided to detect the strain between themedical device and the surrounding tissue and/or between articulatedcomponents of the device/implant itself (e.g., in the case or orthopedicdevices, stent grafts, multiple stents, heart valves, etc.). Suddenincreases in strain may indicate that too much stress is being placed onthe medical device, which may increase damage to the body and/orbreakage, cracking and/or damage to the device.

According to other embodiments, accelerometers are provided in the ISMwhich detect vibration, shock, tilt and rotation of the device/implantand by extension the surrounding tissue itself. According to otherembodiments, sensors are provided in the ISM for measuring surface wear,such as contact or pressure sensors, which may be embedded at differentdepths within the medical device in order to monitor contact of themedical device with surrounding tissues, or degradation of the medicaldevice over time (e.g., in the context of a biodegradable or bioerodibleimplants and devices, or surfaces subject to repeated rubbing or wearsuch as joint surfaces or heart valve leaflets). In other embodiments,ISMs are provided with position sensors, as well as other types ofsensors, which indicate potential problems such as movement, migration,pressure on surrounding anatomical structures, alignment, breakage,cracking and/or bending of the medical device in actual use over aperiod of time.

Within further embodiments, the medical device can contain one or moreISMs with sensors at specified densities in specific locations. Forexample, the medical device can have a density of sensors of greaterthan one, two, three, four, five, six, seven, eight, nine, or tensensors [e.g., accelerometers (acceleration, tilt, vibration, shock androtation sensors), pressure sensors, contact sensors, position sensors,chemical sensors, tissue metabolic sensors, mechanical stress sensorsand temperature sensors, or any combination of these] per squarecentimeter of the device/implant. Within other embodiments, the medicaldevice can have a density of sensors of greater than one, two, three,four, five, six, seven, eight, nine, or ten sensors [e.g.,accelerometers (acceleration, tilt, vibration, shock and rotationsensors), pressure sensors, contact sensors, position sensors, chemicalsensors, tissue metabolic sensors, mechanical stress sensors andtemperature sensors, or any combination of these] per cubic centimeterof the device.

Within certain embodiments of the invention, the medical device isprovided with a specific unique identifying number, and within furtherembodiments, each of the ISMs and/or each of the sensors on, in oraround the medical device each have either a specific uniqueidentification number, or a group identification number [e.g., anidentification number that identifies the sensor as accelerometers(acceleration, tilt, vibration, shock and rotation sensors), pressuresensors, contact sensors, position sensors, chemical sensors, tissuemetabolic sensors, mechanical stress sensors and temperature sensors].Within yet further embodiments, the specific unique identificationnumber or group identification number is specifically associated with aposition on, in or around the medical device.

Within other aspects of the invention methods are provided formonitoring an anatomically-implanted medical device comprising the stepsof transmitting a wireless electrical signal from a location outside thebody to a location inside the body; receiving the signal at a sensorpositioned on, in or around a medical device located inside the body;powering the sensor using the received signal; sensing data at thesensor; and outputting the sensed data from the sensor to a receivingunit located outside of the body.

Within another aspect of the invention methods are provided formonitoring an anatomically-implanted medical device comprising the stepsof transmitting a wireless electrical signal from a location outside thebody to a location inside the body; receiving the signal at ISMimplanted on or within a medical device located inside the body; sensingdata at the sensor; and outputting the sensed data to a location outsideof the body. Within one embodiment, the sensed data may be output to alocation outside of the body by a further implantable module that doesnot contain sensors, or which is designed to coordinate and distributesensed data between one or more ISMs.

Within related aspects of the invention, a subject may have more thanone implanted ISM. Furthermore, multiple ISMs may be ‘connected’, inthat, they can be designed to communicate with each other, and canperform different functions. For example, within one aspect of theinvention methods are provided for monitoring two or moreanatomically-implanted medical devices comprising the steps oftransmitting a wireless electrical signal from a location outside thebody to a location inside the body; receiving the signal at one of aplurality of ISMs implanted on or within a medical device located insidethe body; receiving said signal at ISM implanted on or within a medicaldevice located inside the body; processing said signal and transmittingto one or more other ISMs implanted on or within a medical devicelocated inside the body; sensing data at a sensor in one or more of theother ISMs; and outputting the sensed data from one or more of the otherISMs to the one of a plurality of ISMs; processing the data receivedfrom the one or more of the other ISMs; and outputting processed data toa receiving unit located outside of the body. Within variousembodiments, one of the plurality of ISMs receiving said signal fromoutside the body may not necessarily contain sensors, or be utilized toprovide sensor data, but rather, for example, for signal processing.Within yet other embodiments an implantable module can be utilizedsolely to receive, send and/or store signals. Such implantable modulesmay be utilized to coordinate and transmit signals within a subject, tolocations outside of the subject.

Within other aspects of the invention methods are provided for imaging amedical device as provided herein, comprising the steps of (a) detectingthe location of one or more ISMs having sensors in or on the medicaldevice, any associated anatomical or radiological “landmarks”, and/orassociated medical delivery device or surgical tool; and (b) visuallydisplaying the relative anatomical location of said one or more ISMshaving one or more sensors, such that an image of the medical device iscreated. Within various embodiments, the step of detecting may be doneover time, and the visual display may thus show positional movement overtime. Within certain preferred embodiments the image which is displayedis a three-dimensional image.

The imaging techniques provided herein may be utilized for a widevariety of purposes. For example, within one aspect, the imagingtechniques may be utilized during a surgical procedure in order toensure proper anatomical placement, alignment, deployment andfunctioning of the medical device. Particularly in orthopedicreconstructive surgery (joint replacement) proper alignment and motionis critical, while in trauma surgery and fracture reduction, properalignment and immobilization of the bone fragments is critical toobtaining a good outcome; therefore, allowing the surgeon to be able tosee the implant's position in “real time” (particularly in procedureswhere direct vision is not possible) would be beneficial for achievingproper anatomical placement, alignment and immobilization. Within otherembodiments, the imaging techniques may be utilized post-operatively inorder to examine the medical device, examine the interface withsurrounding tissues, and/or to compare operation, integrity, alignmentand/or movement of the device/implant over time.

The integrity of the medical device can be wirelessly interrogated andthe results reported on a regular basis. This permits the health andstatus of the patient to be checked on a regular basis or at any time asdesired by the patient and/or physician. Furthermore, the medical devicecan be wirelessly interrogated when signaled by the patient to do so(via an external signaling/triggering device) as part of “eventrecording”—i.e. when the patient experiences a particular event (e.g.pain, injury, instability, etc.) she/he signals/triggers thedevice/implant to obtain a simultaneous reading in order to allow thecomparison of subjective/symptomatic data to objective/sensor data.Matching event recording data with sensor data can be used as part of aneffort to better understand the underlying cause or specific triggers ofa patient's particular symptoms. Hence, within various embodiments ofthe invention, methods are provided for detecting and/or recording anevent in a subject with one of the medical devices provided herein,comprising interrogating one of the ISMs on the medical device asprovided herein at a desired point in time. Within one aspect of theinvention, methods are provided for detecting and/or recording an eventin a subject with the medical device as provided herein, comprising thestep of interrogating at a desired point in time the activity of one ormore of the ISMs having sensors within the medical device, and recordingsaid activity. Within various embodiments, interrogation may beaccomplished by the subject and/or by a health care professional. Withinrelated embodiments, the step of recording may be performed with one ormore wired devices, or, wireless devices that can be carried, or worn(e.g., a cellphone, watch or wristband, shoe, and/or glasses).

Within yet other aspects of the invention methods, devices are providedsuitable for transmitting a wireless electrical signal from a locationoutside the body to a location inside the body; receiving the signal atone of the aforementioned sensors positioned on, in or around themedical device located inside the body; powering the sensor using thereceived signal; sensing data at the sensor; and outputting the senseddata from the sensor to a receiving unit located outside of the body.Within certain embodiments the receiving unit can provide an analysis ofthe signal provided by the sensor.

The data collected by the sensors can be stored in a memory locatedwithin the ISM, or on the medical device, or on an associated device(e.g., an associated medical device, or an external device such as acellphone, watch, wristband, and/or glasses). During a visit to thephysician, the data can be downloaded via a wireless sensor, and thedoctor is able to obtain data representative of real-time performance ofthe medical implant, and any associated medical device.

The advantages obtained include more accurate monitoring of the medicaldevice and permitting medical reporting of accurate, in situ, data thatwill contribute to the health of the patient. The details of one or moreembodiments are set forth in the description below. Other features,objects and advantages will be apparent from the description, thedrawings, and the claims. In addition, the disclosures of all patentsand patent applications referenced herein are incorporated by referencein their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a sensor module, according to an embodiment.

FIG. 2 is a diagram of a sensor module that includes multiple sensingchannels, according to an embodiment.

FIG. 3 is a diagram of a sensor-module power system, according to anembodiment.

FIG. 4 is a diagram of a sensor-module data system, according to anembodiment.

FIG. 5 is a diagram of a sensor-module data system, according to anotherembodiment.

FIG. 6 is a diagram of a sensor-module network, according to anembodiment.

FIG. 7 is a schematic illustration of an ISM positioned on a stent graftwithin a patient which is being probed for data and outputting data,according to one embodiment of the invention.

FIG. 8 illustrates the development of an endoleak from the beginning ofthe leak (8A) to substantial formation of the leak (8B). FIGS. 8C and 8Dare a blown up images of 8A and 8B, respectively, which depicts themovement of the ISM sensors during development of the endoleak.

FIG. 9 is a schematic of various types of stent placement, and contactsensors which can aid in this placement. FIG. 9A illustrates a site ofbifurcation with stenosis occurring at multiple points in the vessel.FIG. 9B illustrates a stent with PTCA. FIG. 9C illustrates a stent plusstent deployment (also referred to as a “reverse-T”). FIG. 9Dillustrates a stent plus stent deployment (referred to as “T stenting”).FIG. 9E illustrates a stent plus stent deployment referred to as a“Crush”. FIG. 9F illustrates a stent plus stent deployment referred toas a “Y” or “V”. FIG. 9G illustrates a stent plus stent deploymentreferred to as “Kissing”. FIG. 9H illustrates a stent plus stentdeployment referred to as a “Culotte”.

FIG. 10 is a schematic illustration of an ISM having contact sensorsthat can be utilized to aid and or assist the placement of overlappingstents.

FIG. 11 illustrates the medical imaging of vasculature by an ISM havingsensors which can detect positional movement due to vascular pathology(e.g., restenosis or thrombus formation).

FIG. 12 is a representative example of an implantable hip prosthesis.

FIG. 13 is an illustration of an implanted hip prosthesis having severalISMs.

FIG. 14 is an isometric view of a total knee replacement.

FIG. 15A is an exploded view of the total knee replacement of FIG. 14.FIG. 15B depicts a tibial plate with attached tibial extension. FIG. 15Cdepicts a tibial extension separated from a tibial plate. FIG. 15Ddepicts a tibial extension.

FIG. 16 shows the total knee replacement within a patient.

FIG. 17 is a side view of a total assembled knee with examples ofdifferent sensor locations.

FIG. 18 illustrates one embodiment wherein an ISM having sensors ofvarious types are deployed throughout a balloon catheter.

FIG. 19 illustrates one embodiment wherein sensors of various types aredeployed by an ISM on the surface of an aesthetic (breast) implant.

FIG. 20 illustrates one embodiment called vertebroplasty wherein an ISMis placed into the body of the body of a vertebrae, followed byinjection of bone cement (without the use of a balloon). These Figuresillustrate one embodiment wherein, a hole is created in the vertebralbody (FIG. 20A) through a bone tunneling catheter; introduction of anISM (FIG. 20B); and introduction of a delivery device (FIG. 20C) whichallows injection of the bone cement directly into the collapsed bone.The compression fracture is corrected and supported through theinjection of bone cement into the vertebral body (as shown in FIGS. 20Dand 20E) to restore the normal height of the vertebra.

FIG. 21 illustrates one embodiment wherein one or more ISMs are placedon and/or within a kyphoplasty balloon.

FIG. 22 illustrates a variety of spinal fusion implants, includingpedicle screws affixed to rods (FIG. 22A), and a spinal plate retainedby screws (FIG. 22B).

FIG. 23 illustrate a spinal (interbody) cage having an ISM.

FIG. 24 illustrate an artificial intervertebral disc having an ISM.

FIG. 25 illustrates the use and placement of an external fixation device(including the use of screws, pins and clamps) on a bone (FIG. 25A), andan external fixation device having several ISMs placed on it (FIG. 25B)implanted on the arm (FIG. 25C).

FIG. 26 illustrates a variety of braces and slings. FIG. 26A illustratesa knee brace having ISMs; FIG. 26B a neck brace.

FIG. 27 illustrates one embodiment wherein an ISM is placed on or withinseveral pins (Steinmann pins) inserted to reduce a humeral fracture.

FIG. 28 illustrates one embodiment wherein an ISM is placed on and/orwithin several K-wires (Kirschner wires) inserted to reduce a radialfracture.

FIGS. 29A and 29B illustrate representative dynamic hip screws havingISMs, including cortical screws inserted into the sideplate (FIG. 29A),and an illustration of the device inserted into a subject (FIG. 29B).FIG. 29C illustrates an embodiment wherein ISMs are placed on arepresentative fixation plate.

FIG. 30 illustrates representative intramedullary rods or nails,including an intramedullary nail (FIG. 30A) having ISMs, and placementof an intramedullary nail having ISMs in the tibia (FIG. 30B).

FIG. 31A illustrates a representative bileaflet mechanical valve with anISM. FIG. 31B illustrates a tilting disc mechanical valve with an ISM.

FIG. 32A illustrates a representative porcine valve with an ISM. FIG.32B illustrates a representative bovine valve with an ISM.

FIG. 33A illustrates an ISM on an expanded (stent) scaffold, and FIG.33B illustrates a representative percutaneous heart valve with an ISMand a representative delivery system with an ISM.

FIG. 34A illustrates an ISM on a balloon delivery device for aballoon-expandable percutaneous heart valve, as well as an ISM on theballoon itself. FIG. 34B illustrates an ISM on a balloon-expandablepercutaneous heart valve.

FIG. 35 is a schematic illustration of an ISM on a medical device asdescribed herein within a subject which is being probed for data andoutputting data, according to one embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Briefly stated the present invention provides a variety of medicaldevices and implants that can be utilized to monitor the placement,location, anatomy, alignment, immobilization, performance, healing,integrity, wear, side effects, and/or efficaciousness of the medicaldevice, and any associated medical devices and or device deliveryinstruments. Prior to setting forth the invention however, it may behelpful to an understanding thereof to first set forth definitions ofcertain terms that are used hereinafter.

“Medical device” refers to an instrument, apparatus, constructed elementor composition, machine, implement, or similar or related article thatcan be utilized to diagnose, prevent, treat or manage a disease or othercondition(s). The medical devices provided herein may, depending on thedevice and the embodiment, be implanted within a subject, utilized todeliver a device to a subject, or, utilized externally on a subject. Inmany embodiments the medical devices provided herein are sterile, andsubject to regulatory requirements relating to their sale and use.Representative examples of medical devices and implants include, forexample, cardiovascular devices and implants such as implantablecardioverter defibrillators, pacemakers, stents, stent grafts, bypassgrafts, catheters and heart valves; orthopedic implants (e.g., total orpartial arthroplastic joints such as hip and knee prosthesis); spinalimplants and hardware (spinal cages, screws, plates, pins, rods andartificial discs); a wide variety of medical tubes, cosmetic and/oraesthetic implants (e.g., breast implants, fillers); a wide variety ofpolymers, bone cements, bone fillers, scaffolds, and naturally occurringmaterials (e.g., heart valves, and grafts from other naturally occurringsources); intrauterine devices; orthopedic hardware (e.g., casts,braces, tensor bandages, external fixation devices, tensors, slings andsupports) and internal hardware (e.g., K-wires, pins, screws, plates,and intramedullary devices (e.g., rods and nails)); cochlear implants;dental implants; medical polymers, a wide variety of neurologicaldevices; and artificial intraocular eye lenses.

“Sensor” refers to a device that can be utilized to measure one or moredifferent aspects of a body tissue (anatomy, physiology, metabolism,and/or function) and/or one or more aspects of the medical device.Representative examples of sensors suitable for use within the presentinvention include, for example, fluid pressure sensors, fluid volumesensors, contact sensors, position sensors, pulse pressure sensors,blood volume sensors, blood flow sensors, chemistry sensors (e.g., forblood and/or other fluids), metabolic sensors (e.g., for blood and/orother fluids), accelerometers, mechanical stress sensors and temperaturesensors. Within certain embodiments the sensor can be a wireless sensor,or, within other embodiments, a sensor connected to a wirelessmicroprocessor. Within further embodiments one or more (including all)of the sensors can have a Unique Sensor Identification number (“USI”)which specifically identifies the sensor and/or a Unique DeviceIdentification number (“UDI”) with which the sensors can provide uniqueinformation of the associated Medical device for tracking purposes ofthe Medical Device manufacturer, the health care system, and regulatoryrequirements.

A wide variety of sensors (also referred to as MicroelectromechanicalSystems or “MEMS”, or Nanoelectromechanical Systems or “NEMS”, andBioMEMS or BioNEMS, see generally https://en.wikipedia.org/wiki/MEMS)can be utilized within the present invention. Representative patents andpatent applications include U.S. Pat. Nos. 7,383,071, 7,450,332;7,463,997, 7,924,267 and 8,634,928, and U.S. Publication Nos.2010/0285082, and 2013/0215979. Representative publications include“Introduction to BioMEMS” by Albert Foch, CRC Press, 2013; “From MEMS toBio-MEMS and Bio-NEMS: Manufacturing Techniques and Applications by MarcJ. Madou, CRC Press 2011; “Bio-MEMS: Science and EngineeringPerspectives, by Simona Badilescu, CRC Press 2011; “Fundamentals ofBioMEMS and Medical Microdevices” by Steven S. Saliterman, SPIE-TheInternational Society of Optical Engineering, 2006; “Bio-MEMS:Technologies and Applications”, edited by Wanjun Wang and Steven A.Soper, CRC Press, 2012; and “Inertial MEMS: Principles and Practice” byVolker Kempe, Cambridge University Press, 2011; Polla, D. L., et al.,“Microdevices in Medicine,” Ann. Rev. Biomed. Eng. 2000, 02:551-576;Yun, K. S., et al., “A Surface-Tension Driven Micropump for Low-voltageand Low-Power Operations,” J. Microelectromechanical Sys., 11:5, October2002, 454-461; Yeh, R., et al., “Single Mask, Large Force, and LargeDisplacement Electrostatic Linear Inchworm Motors,” J.Microelectromechanical Sys., 11:4, August 2002, 330-336; and Loh, N. C.,et al., “Sub-10 cm³ Interferometric Accelerometer with Nano-gResolution,” J. Microelectromechanical Sys., 11:3, June 2002, 182-187;all of the above of which are incorporated by reference in theirentirety.

Within various embodiments of the invention the sensors described hereinmay be placed at a variety of locations and in a variety ofconfigurations, on the inside of a medical device, within the body ofthe medical device, on the outer surfaces (or inner surfaces) of themedical device, between the medical device and other medical devices orimplants, and/or between the medical device and any device that mightcarry or deliver it (e.g., a delivery device, injection device, orsurgical instrument). When the phrase “placed in a medical device” or“placed in a medical implant” is utilized, it should be understood torefer to any of the above embodiments (or any combination thereof)unless the context of the usage implies otherwise.

The sensors may be placed in the medical device alone, or along with anassociated medical device which might be utilized in a desired surgicalprocedure. For example, within certain embodiments, the medical deviceand/or medical device kit comprises sensors at a density of greater than1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per squarecentimeter. Within other aspects, the medical device and/or medicaldevice kit comprises sensors at a density of greater than 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or greater than 10 sensors per cubic centimeter. Withineither of these embodiments, there can be less than 50, 75, 100, or 100sensors per square centimeter, or per cubic centimeter. Within variousembodiments, at least one or more of the sensors may be placed randomly,or at one or more specific locations within the medical device, medicaldevice, or kit as described herein.

In various embodiments, the sensors may be placed within specificlocations and/or randomly throughout the medical device and/orassociated devices. In addition, the sensors may be placed in specificpatterns (e.g., they may be arranged in the pattern of an X, as oval orconcentric rings around the orthopedic implant and/or associateddevices).

“Implantable Sensor Module” or “ISM” is a sensing device which isconfigured to be implanted in, or otherwise attachable to, a livingsubject, such as a human subject, and is configured to sense one or morephysical quantities, to generate a signal that represents the sensedquantity, and to transmit the signal to a remote receiver. The ISM mayhave one or more sensors as provided above. The ISM may be implantedinto a subject directly, or, within one or more medical devices whichare implanted within a subject. Within an embodiment, the signal maycontain information encoded to represent one or more of a magnitude,phase, and type of the sensed physical quantity.

Within one embodiment of the invention, the ISM is a self-containedmodule having one or more sensors as described herein, a sensorinterface, a processor interface, battery management, and a wirelessinterface. Within preferred embodiments of the invention the ISM will beless than 5, 4, 3, 2, or 1 cubic centimeter in size, and morepreferably, less than 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.9,0.8. 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 cubic centimeters in size.Within various embodiments the ISM can be comprised of a solid outercore, or composed of flexible materials (e.g., flexible/malleablealloys, a degradable or non-degradable outer polymeric surface). Withinrelated embodiments, the ISM can be comprised of flexible circuitry(including for example, single and double-sided flexible circuits.Within certain embodiments the ISM may be relatively square and solid,and yet with in other embodiments very thin, pliable and lengthy (ascompared to its width and/or height). It can be constructed for a numberof different applications (e.g., for insertion, attachment orimplantation into any of the medical devices or implants providedherein).

Representative Embodiments of Medical Devices and Medical Uses ofSensor-Containing Medical Devices

In order to further understand the various aspects of the inventionprovided herein, the following sections are provided below:

-   -   A. Implantable Sensor Modules;    -   B. Implantable Medical Devices (including B1—Stent Grafts;        B2—Stents; B3—Hips; B4—Knees; B5—Tubes; B6—Implants; B7—Spinal        Implants; B8—Orthopedic Hardware; B9—Polymers; B10—Heart Valves;        and B11 Methods of Manufacture);    -   C. Use of Medical Devices Having ISMs to Deliver Therapeutic        Agent(s);    -   D. Methods for Monitoring Infection in Medical devices;    -   E. Further Uses of ISM-containing Medical Devices or Implants in        Healthcare;    -   F. Generation of Power from Medical Devices or Implants;    -   G. Medical Imaging and Self-Diagnosis of Assemblies Comprising        Medical Devices or Implants, Predictive Analysis and Predictive        Maintenance;    -   H. Methods of Monitoring Assemblies Comprising Medical Devices        or Implants; and    -   I. Collection, Transmission, Analysis, and Distribution of Data        from Assemblies Comprising Medical Devices or Implants.

A. Implantable Sensor Modules

As noted above, the present invention provides ISM's suitable forimplantation in, or otherwise being attached (internally or externally)to a living subject [e.g., by implantation into a medical device and/orattachment to a medical device which is then surgically placedinternally (hip and knee replacements, stents, heart valves, etc.) orapplied to the outside of the body (casts, braces, tensors, externalfixation devices, etc.)]. FIG. 1 is a diagram of a sensor module 10,according to one embodiment of the invention. The sensor module 10 isconfigured to be implantable in, or otherwise attachable to, a livingsubject, such as a human subject, and is configured to sense a physicalquantity, to generate a signal that represents the sensed quantity, andto transmit the signal to a remote receiver (not shown in FIG. 1) forprocessing. The ISM may be implanted into a subject directly, within oneor more medical devices which are implanted within a subject, or, within(or attached to) a medical device that is affixed to the outside of thebody. Within an embodiment, the signal may contain information encodedto represent one or more of a magnitude, phase, and type of the sensedphysical quantity.

The sensor module 10 may be suitable for applications that call for thesensing of one or more biological quantities (biological quantities arephysical quantities) of the subject in which the module is implanted orto which the module is attached. For example, the sensor module 10 maysense one or more of the electrical signals generated by the subject'sheart, and may generate a signal that represent an electrocardiogram ofthe heart; the device that receives the signal may then generate avisual representation of the electrocardiogram in response to thesignal. Other applications include, but are not limited to, sensing oneor more parameters (e.g., contact, pressure, position, movement, wear,stability, level of bone attachment) related to an artificial joint,brain activity, organ function, blood flow, digestion, and/or drugeffectiveness.

The sensor module 10 includes a power supply 12, one or more sensors 14,a sensor interface 16, a sensor-module controller 18, a wirelessinterface 20, and an antenna 22. The supply 12, sensor(s) 14, channel16, controller 18, interface 20, and antenna 22 may be disposed on oneor more integrated-circuit dies that are respectively disposed in one ormore integrated-packages to form one or more integrated circuits (ICs);and these one or more ICs may be disposed in (not shown in FIG. 1), isimplantable in, or otherwise attachable too, a subject. Or, thesensor(s) 14 and the antenna 20, or any other of the afore-mentionedcomponents, may be not be disposed on an IC die, but may be discretecomponents.

The power supply 12 is configured to generate a regulated supply signal(e.g., a regulated supply voltage V_(o)) to power the other componentsof the sensor module 10, and includes an energy harvester 24, a batterycharger 26, a power coil 28, a protector 30, and a battery receptacle 32for receiving a battery 34, according to an embodiment.

The regulated supply voltage V_(o) may be in, for example, anapproximate range of 1-24 Volts (V), according to an embodiment.Furthermore, although not shown in FIG. 1, the power supply 12 maygenerate more than one regulated supply signal.

The energy harvester 24 is configured to convert an environmentalstimulus into an electrical current or voltage for charging the battery34, according to an embodiment. For example, the harvester 24 mayconvert, into a battery-charging electrical current or voltage, one ormore of body heat from the subject in which the sensor module 10 isimplanted or otherwise attached, kinetic energy generated by thesubject's movement, changes in pressure (e.g., barometric pressure orpressure within the subject, such as the subject's blood pressure),energy generated by an electrochemical reaction within the subject'sbody, radio-frequency (RF) energy (e.g., ambient RF transmissions), andlight.

The battery charger 26 includes the power coil 28, which is configuredto generate a voltage and current in response to a near magnetic fieldgenerated by a power unit (not shown in FIG. 1), according to anembodiment; such near-magnetic-field charging may be similar to atechnique for powering a smart card. For example, the battery charger 26and coil 28 may be used to charge the battery 34 while the energyharvester 24 is unable to generate enough energy to charge the batteryto a voltage level sufficient for proper operation of the sensing module10.

The protector 30 protects the battery 34 from overcharging or otherconditions that may damage the battery, and also protects the powersupply 12 in case a load current drawn from the regulated voltage V_(o)(or from another regulated supply signal that the power supplygenerates) exceeds a predetermined safe threshold. The protector 30 mayalso monitor temperature of battery 34 and make appropriate adjustmentsof safe thresholds. For example, the protector 30 may disable the energyharvester 24 and the battery charger 26 if the voltage across thebattery 34 exceeds a predetermined safe threshold, and may also generatesome type of alarm to indicate a malfunction. And, the protector 30 maylimit the load current drawn from V_(o) (or from another regulatedsupply signal) to a safe limit, or may otherwise disable the powersupply 12 if the load current exceeds a predetermined safe threshold;for example, the protector may implement such a limit or disabling ifthe node carrying V_(o) is short-circuited to ground.

And the battery 34 may be any type of rechargeable battery, such as alithium-ion battery, that is suitable for use in an electronic devicethat is implantable in, or otherwise attachable to, a biologicalsubject.

Still referring to FIG. 1, the one or more sensors 14 are eachconfigured to sense a respective physical quantity within, or otherwiseinfluenced by, the body of the subject in which the module 10 isimplanted or to which the module is attached, and are each configured togenerate a respective sensor signal that represents one or more of amagnitude, phase (if applicable), and type of the respective sensedquantity. Examples of such a physical quantity include, but are notlimited to, a relative or absolute position of the sensor module 10, amovement (e.g., acceleration, velocity, rotation) of the sensor module,and the following quantities in the vicinity of the sensor module: anelectric field, voltage, or current, a magnetic field, a temperature, apressure (e.g., blood pressure), radiation, electrical conductivity, anoptical intensity, a spatial or temporal differential in the physicalquantity (e.g., a temperature differential, a pressure differential, ora voltage differential), a biological marker (e.g., a tumor marker,bacterial marker or DNA fragment), a chemical composition of asubstance, and a chemical reaction or a byproduct thereof. Examples ofthe one or more sensors 14 include, but are not limited to, thefollowing types of sensors: global-positioning-system (GPS),accelerometer, Hall-effect, electrical (e.g., current, voltage, andconductivity), magnetic, thermal, pressure, radiation, optical,quantity-differential, capacitive, inductive, and microelectromechanical(MEMS). And examples of the sensor signal include an analog or digitalvoltage or current.

The sensor interface 16, which, together with the sensor(s) 14, forms asensor channel 36, includes a power-management circuit 38, an oscillator40, an amplifier 42, a signal conditioner 44, an optionalanalog-to-digital converter (ADC) 46, and a control circuit 50,according to an embodiment.

The power-management circuit 38 is configured to convert V_(o) from thepower supply 12 into one or more other supply voltages or supplycurrents for the sensor 14 and the circuits of the sensor interface 16.The power manager 38 may provide power to the sensor using a conductoror by induction using a coil. Sensor 14 may provide a signal to sensorinterface 16 using one or more conductors or by induction using a coil.The coil used to provide power to sensor 14 may be the same coil thatreceives the signal from sensor 14. Alternatively, the coil used toprovide power to sensor 14 may be separate from the coil that receives asignal from sensor 14.

The oscillator 40 generates one or more clock signals for the digitaland mixed-signal circuits of the sensor interface 16, and, depending onthe types of the one or more sensors 14, may generate an analogreference signal for the sensor(s) 14. For example, a sensor 14 maygenerate a sensor signal by modifying one or more of the frequency,amplitude, and phase of such an analog reference signal in response to arespective physical quantity. Examples of the oscillator 40 include aring oscillator, an operational-amplifier-based oscillator, or otherdigital or analog oscillator.

The amplifier 42 is configured to amplify the sensor signal generated bya sensor 14, according to an embodiment. Although shown as a having asingle-ended input and a single-ended output, the amplifier 42 may haveone or both of a differential input and a differential output. Examplesof the amplifier 42 include an operational amplifier (e.g., having afeedback configuration), a transconductance (g_(m)) amplifier (e.g.,having an open-loop configuration), and a low-noise amplifier (LNA). Ifthere are more than one sensor 14, then the sensor interface 16 mayinclude a respective amplifier 42 for each sensor, or a mux that selectswhich sensor output is input to amplifier 42. The gain of amplifier 42may be controlled by one or more of the signal conditioner 44, the ADC46.

The signal conditioner 44 is configured to condition the amplifiedsensor signal from the amplifier 42 for reception by the ADC 46 ifpresent, or for reception by the sensor-module controller 18 if the ADCis not present. For example, the conditioner 44 may be configured toadjust the amplitude and the DC offset of the amplified sensor signal sothat it is compatible with the dynamic input range of the ADC 46, toremove noise from, or to otherwise filter, the amplified sensor signal,or to equalize the amplified sensor signal. In addition, the signalconditioner 44 may be configured to add error-correction coding (ECC) tothe amplifier sensor signal.

If present, the ADC 46 is configured to convert the conditioned sensorsignal from the analog domain to the digital domain; but if the sensor14 is configured to generate the sensor signal in the digital domain,then the amplifier 42 and the signal conditioner 44 may be digitalcircuits, and the ADC 46 may be omitted as described above.

And the control circuit 50 is configured to control the operations ofone or more of the power manager 38, oscillator 40, amplifier 42, signalconditioner 44, and ADC 46, and may be configured to control theoperations of one or more other components of the sensor interface 16.For example, the control circuit 50 may include, or be coupled to, amemory (not shown in FIG. 1) that stores configuration data orprogramming instructions for the sensor(s) 14 or for the sensorinterface 16, and may configure the sensor(s) 14 or the interface 16 inresponse to this data or these instructions upon power up of the sensormodule 10. Furthermore, the control circuit 50 may be configured tocontrol communications between the interface 16 and the sensor-modulecontroller 18.

Still referring to FIG. 1, the sensor-module controller 18 is configuredto control the operations of the power supply 12, the sensor channel 36,the wireless interface 20, and other components of the sensor module 10,according to an embodiment, and includes a microcontroller ormicroprocessor 52, a memory 54, and a co-controller or co-processor,such as a digital-signal processor (DSP) 56, according to an embodiment.For clarity, hereinafter the microcontroller/microprocessor 52 isreferred to as a microcontroller, it being understood that themicrocontroller may instead be a microprocessor.

The microcontroller 52, in cooperation with the DSP 56, is configured toprocess the signal from the sensor channel 36, to generate data from theprocessed signal, and to condition the signal for transmission by thewireless interface 20. For example, if the sensor 14 measurestemperature, then the microcontroller 52 may convert the signal from thesensor interface 16 into a temperature value in units of Fahrenheit orCelsius; or, if the sensor measures pressure, then the microcontrollermay convert the signal from the sensor interface into a pressure valuein units of Pascal.

The memory 54 may include volatile memory and non-volatile memory,according to an embodiment. For example, the volatile memory may beconfigured to store the operating system and one or more applicationsexecuted by the microcontroller 52, and the non-volatile memory may beprogrammed to store configuration information for the sensor module 10,such configuration information including, but not limited to, the typeof the sensor 14, the frequency signal generated by the oscillator, thegains of the amplifier 42 and the signal conditioner 44, and the levelof the voltage V_(o) generated by the power supply 12.

And the wireless interface 20 is configured to receive the data from thesensor-module controller 18, to modulate one or more carrier signalswith the data, and to transmit, via the antenna 22, the modulatedcarrier signal(s) to a remote device (not shown in FIG. 1) for use by,e.g., the subject in which the sensor module 10 is implanted orattached, or to his/her physician. For example, the wireless interface20 may be configured to operate according to a specification such as,but not limited to, one of the following specifications: Bluetooth®,near-field communication (NFC), ZigBee (IEEE 802.15), WiFi, wirelesslocal area network (WLAN, IEEE 802.11).

Furthermore, the wireless interface 20 may be configured to receive asignal from a remote device (not shown in FIG. 1) via the antenna 22,and to provide this signal to the supply-module controller 18. Forexample, such a signal may include sensor-module configuration data orprogram instructions, or may include a request that the sensor-module 10transmit specified data to the remote device. Examples of the remotedevice include, but are not limited to, a smart phone or tablet computer(FIG. 4), a computer system (FIG. 5), or another sensor module 10 (FIG.6).

Still referring to FIG. 1, the operation of the sensing module 10 duringa sensing mode is described, according to an embodiment.

The power supply 12 generates the regulated supply voltage V_(o) (andperhaps one or more other regulated supply signals) from the voltageV_(BATT) across the battery 34. For example, if the battery voltageV_(BATT)>V_(o), then the power supply 12 steps down V_(BATT) to V_(o);the power supply may include a buck converter to perform such a voltagestep down. Alternatively, if V_(BATT)<V_(o), then the power supply 12steps up V_(BATT) to V_(o); the power supply may include a boostconverter to perform such a voltage step up.

The sensor 14 senses a physical quantity that the sensor is configuredto sense, and provides to the sensor interface 16 a sensor signal thatrepresents the sensed quantity.

The sensor interface 16 amplifies, conditions, and, if the sensor signalis an analog signal, converts the conditioned sensor signal to thedigital domain via the amplifier 42, signal conditioner 44, and ADC 46,respectively.

The sensor-module controller 18 processes the conditioned (and possiblyADC converted) sensor signal from the interface 16, and generates datarepresenting the sensed quantity. The controller 18 may store thegenerated data in the memory 54 for later retrieval, or may provide thedata to the wireless interface 20.

And if the sensor-module controller 18 provides the data to the wirelessinterface 20, then the wireless interface modulates one or more carrierssignals with the data from the sensor-module controller 18, generates atransmission signal from the one or more carriers signals, and transmitsthe transmission signal to a remote device (not shown in FIG. 1) via theantenna 22.

Still referring to FIG. 1, the operation of the sensing module 10 duringa data-receiving mode is described, according to an embodiment.

The power supply 12 generates the regulated supply voltage V_(o) (andperhaps one or more other regulated supply signals) from the voltage V_(BATT) across the battery 34 as it does during the above-describedsensing mode.

The wireless interface 20 senses a signal being received by the antenna22 and notifies the sensor-module controller 18.

In response to the wireless interface 20 sensing the received signal,the sensor-module controller 18 instructs the wireless interface todemodulate, and, if necessary, decode, the received signal, recover thedata from the signal, and provide the data to the sensor-modulecontroller.

The sensor-module controller 18 analyzes the recovered data, and takesappropriate action. For example, if the data is configuration data, thenthe sensor-module controller 18 may load this data into a non-volatileportion of the memory 54, and initiate a configuration cycle so as toconfigure, or reconfigure, one or more portions of the sensing module 10in response to the configuration data. Or, if this data is a command,then the sensor-module controller 18 may execute the command. Forexample, if the command is a request for the sensor module 10 to sendspecified other data to a remote device (not shown in FIG. 1), then thecontroller 18 sends the requested data via the wireless interface 20,which modulates one or more carrier signals with the requested data,generates a transmission signal from the one or more carriers signals,and transmits the transmission signal to a remote device via the antenna22 as described above in conjunction with the sensing mode.

Still referring to FIG. 1, alternate embodiments of the sensor module 10are contemplated. For example, any of the functions performed by thesensor module 10 may be performed either by dedicated hardware,configurable hardware [e.g., a field-programmable gate array (FPGA)], amicroprocessor or microcontroller executing program instructions, or acombination or sub-combination of dedicated hardware, configurablehardware, and a microprocessor or microcontroller executing programinstructions. Furthermore, although the sensor module 10 is described asincluding components disposed in a single housing, the sensor module mayinclude multiple housings/pieces linked together wirelessly and/oroperating independently. Moreover, although described as beingimplantable or otherwise attachable to a subject, the sensor module 10may be configured to be disposed remotely from a subject, or to beingested or inhaled by a subject.

FIG. 2 is a diagram of a sensor module 60, according to an embodiment.The sensor module 60 is similar to the sensor module 10 of FIG. 1,except that the sensor module 60 includes multiple sensor channels 36₁-36 _(n), each of which may have one or more sensors 14.

FIG. 3 is a diagram of a sensor-module power-transfer system 70,according to an embodiment.

The system 70 includes the sensor module 10 of FIG. 1, and includes asensor power unit 72 having a power coil 74. The sensor power unit 72 isconfigured to provide energy to the sensor module 10 in a manner similarto the manner in which a smart-card reader may power a smart card.

In operation during a power-transfer mode of the sensor module 10, onefirst positions the power coil 74 in near-field proximity (e.g., in anapproximate range of 0-4 inches) to the power coil 28 of the sensormodule.

Next, one activates the power unit 72, which generates, across the coil74, an alternating (AC) voltage, which causes an alternating (AC)current to flow through the coil.

Because the power coil 74 is in near-field proximity to the power coil28, the coils are magnetically (i.e., inductively) coupled such thateach coil acts as a respective winding of a transformer. This couplingoccurs even though the coil 28 may be implanted in a subject such thatitems like air, clothing, and biological materials (e.g., skin or othertissue, and blood) separate the coils 28 and 74.

Due to the inductive coupling between the coils 28 and 74, the magneticflux generated by the AC current flowing through the coil 74magnetically induces an AC current through, and an AC voltage across,the coil 28.

Consequently, the charger 26 of the power supply 12 (FIG. 1) isconfigured to use the induced AC current through, and the induced ACvoltage across, the coil 28 to charge the battery 34 (FIG. 1), or thepower supply 12 may include circuitry that is configured to directlypower the sensor module 10 from the induced AC current and voltage.

After the power-transfer mode is complete, one deactivates the sensorpower unit 72 and removes the coil 74 from near-field proximity with thecoil 28.

Still referring to FIG. 3, alternate embodiments of the sensor-modulepower system 70 are contemplated. For example, the system 70 may includethe sensor module 60 of FIG. 2 instead of the sensor module 10 ofFIG. 1. Or the system 70 may include more than one sensor module (e.g.,one or more of one or both sensor modules 10 and 60) or more than onepower unit 72. Furthermore, as described above in conjunction with FIG.1, while the coil 74 is not in near-field proximity with the sensormodule 10, or while the power unit 72 is inactive, the power supply 12of FIG. 1 may convert other sources of energy (e.g., kinetic energy,temperature-induced energy, pressure-induced energy) into a voltage andcurrent suitable to charge the battery 34 (FIG. 1) or to power thesensor module 10.

FIG. 4 is a diagram of a sensor data system 80, according to anembodiment.

The sensor data system 80 includes the sensor module 10 of FIG. 1 and aremote data-receiving device 82.

The remote data-receiving device 82 may be, or include, a smart phone ortablet computer having circuitry sufficient to receive, demodulate, andrecover sensor data from the wireless signal that the sensor module 10transmits via the antenna 22. And the device 82 may also be configuredto analyze, or otherwise process, the recovered sensor data. Forexample, the device 82 may be configured to display the recovered sensordata (e.g., an electrocardiogram), to make a recommendation or warning(e.g., “blood sugar level low”) in response to the sensor data, or tostore the sensor data for later processing by the device 82 or byanother device or for later review by a medical professional.

Still referring to FIG. 4, the operation of the sensor data system 80 isdescribed, according to an embodiment.

First, the device 82 notifies the sensor module 10 that the device wouldlike to receive sensor data, or the sensor module notifies the devicethat the sensor module would like to send sensor data to the device.

Next, the sensor module 10 and the device 82 establish communicationsusing, e.g., a handshake technique.

Then, the sensor module 10 transmits a signal including the sensor dataaccording to a communications protocol such as Bluetooth® or NFC.

Next, the device 82 receives the transmitted signal and recovers thedata therefrom.

Then, the sensor module 10 notifies the device 82 when all of the datahas been transmitted.

Next, the device 82 notifies the sensor module 10 that it has receivedall of the data, or that it needs the sensor module to resend some orall of the data (e.g., due to a communications error).

Then, the sensor module 10 notifies the device 82 if it has more data tosend, or the device requests additional data from the sensor module. Ifthe sensor module 10 sends additional data, then it does so according tothe same procedure described above.

After the sensor module 10 is finished transmitting all available orrequested data, it notifies the device 82, which acknowledges thisnotification to the sensor module.

Next, the sensor module 10 and the device 82 cease communicating withone another.

Then, the device 82 may display a representation of the recovered data,may make a recommendation or warning based on the recovered data, maytransmit the data to another device, such as to a computer system at adoctor's office, via, e.g., a phone system, or may store the data forlater access.

Still referring to FIG. 4, alternate embodiments of the sensor datasystem 80 are contemplated. For example, the system 80 may include thesensor module 60 of FIG. 2 instead of the sensor module 10 of FIG. 1. Orthe system 80 may include more than one sensor module (e.g., one or moreof one or both sensor modules 10 and 60) or more than one device 82.Furthermore, the data that the sensor module 10 sends to the remotedevice may be sensor-module-status data instead of, or in addition to,sensor data. Moreover, the remote device 82 may send data, such asconfiguration data or command data, to the sensor module 10.

FIG. 5 is a diagram of a sensor data system 90, according to anembodiment.

The sensor data system 90 can be similar to the sensor data system 80 ofFIG. 4, except that instead of the device 82, the system 90 includes acomputer system 92 having a communication interface (e.g., a Bluetooth®interface) 94. The computer system 92 and the interface 94 can beconfigured to perform, together or separately, the operations that thedevice 82 of FIG. 4 is described as performing.

Still referring to FIG. 5, alternate embodiments of the sensor datasystem 90 are contemplated. For example, the system 90 may include thesensor module 60 of FIG. 2 instead of the sensor module 10 of FIG. 1. Orthe system 90 may include more than one sensor module (e.g., one or moreof one or both sensor modules 10 and 60) or more than one computersystem 92. Furthermore, the data that the sensor module 10 sends to thecomputer system 92 may be sensor-module-status data instead of, or inaddition to, sensor data. Moreover, the computer system 92 may senddata, such as configuration data or command data, to the sensor module10.

FIG. 6 is a diagram of a sensor-module network 100, according to anembodiment.

The network 100 includes multiple sensor modules 10 (FIG. 1), which areconfigured to communicate with one another using, e.g., ZigBee oranother multi-node wireless-network protocol. For example, the sensormodules 10 may be implanted in, or otherwise attached to, a samesubject, or in or to two or more different subjects.

Still referring to FIG. 6, the operation of the sensor-module network100 is described, according to an embodiment.

First, when an initiating one of the modules 10 in the network 100 isready to communicate with a responding one of the modules, theinitiating module first determines if the communication channel isclear, i.e., that there are no other sensor modules currently using thechannel for inter-module communications.

If the initiating module 10 determines that the communication channel isclear, then it notifies the responding sensor module that the initiatingsensor module would like to receive sensor data or other data from theresponding sensor module, or the initiating sensor module notifies theresponding sensor module that the initiating sensor module would like tosend sensor data or other data to the responding sensor module.

Next, the initiating and responding sensor modules 10 establishcommunications using, e.g., a handshake technique, and also inform theremaining sensor modules that the communication channel is being used.

Then, the initiating sensor module 10 transmits a signal including thesensor data; or, if the initiating sensor module is requesting data,then the responding sensor module transmits a signal to the initiatingsensor module.

Next, the one of the initiating and responding sensor module 10 that isto receive the data receives the transmitted signal and recovers thedata therefrom.

Then, the transmitting one of the initiating and responding sensormodules 10 notifies the receiving one of the initiating and respondingsensor modules when all of the data has been transmitted.

Next, the receiving one of the initiating and responding sensor modules10 notifies the transmitting one of the initiating and responding sensormodules that it has received all of the data, or that if needs thetransmitting one of the initiating and responding sensor modules toresend some or all of the data (e.g., due to a communications error).

Then, the transmitting one of the initiating and responding sensormodules 10 notifies the receiving one of the initiating and respondingsensor modules if it has more data to send, or the receiving one of theinitiating and responding sensor modules requests additional data fromthe transmitting one of the initiating and responding sensor modules. Ifthe transmitting one of the initiating and responding sensor modules 10sends additional data, then it does so according to the same procedure.

After the transmitting one of the initiating and responding sensormodules 10 is finished transmitting all available or requested data, itnotifies the receiving one of the initiating and responding sensormodules, which acknowledges this notification to the transmitting one ofthe initiating and responding sensor modules.

Next, the initiating and responding sensor modules 10 ceasecommunicating with one another.

Then, the receiving one of the initiating and responding sensor modules10 may use the recovered data for any suitable purpose.

Still referring to FIG. 6, alternate embodiments of the sensor-modulenetwork 100 are contemplated. For example, the network 100 may includesensor modules 60 of FIG. 2 instead of sensor modules 10 of FIG. 1. Orthe network 100 may include one or more of one or both sensor modules 10and 60.

Still referring to FIG. 6, alternate embodiments of the sensor-modulenetwork 100 are contemplated. For example, the network 100 may employ amaster-slave protocol where only one of the sensor modules serves asmaster, sending and receiving data to a plurality of sensorssimultaneously or one at a time, and receiving data from sensor modulesone at a time; whereas the master sensor module, in the alternative, maynot contain any sensors. The master sensor module sends and receivesdata from a transceiver outside the body.

B. Temporary and Permanent Implantable Medical Devices and their Use

B.1. Stent Grafts 0.401

Within one embodiment of the invention, stent grafts are provided havingone or more ISMs as described herein. Briefly, “stent graft”, asutilized herein, refers to a device comprising a graft or covering(composed of a textile, polymer, or other suitable material such asbiological tissue) which maintains the flow of fluids (e.g., blood) fromone portion of a vessel to another, and an endovascular scaffolding orstent (including expandable and balloon-inflatable stent structures)that holds open a body passageway and/or supports the graft or covering.Endovascular stent grafts may be used to treat a variety of vascularconditions, including treating abdominal aortic aneurysms and thoracicaortic aneurysms (referred to as “EVAR”—endovascular aortic aneurysmrepair), atherosclerosis, peripheral vascular disease or other vasculardiseases. Endovascular stent grafts are also used in dialysis grafts anddialysis fistulas to treat obstructions or aneurysms that occur at thesite of vascular access in hemodialysis patients. Non-vascular stentgrafts can be used in a variety of other body passageways such as theesophagus, colon, bile duct, urethra and ureter to name a few examples.Within certain embodiments, the stent graft has at least two openings(and within further embodiments, three or more openings), an outer(adluminal) surface, and an inner (luminal) surface. Within certainembodiments the stent graft is an “articulated” or “segmented” stentgraft; these multi-component stent grafts are inserted as separatesegments which are then assembled inside the body (artery or other bodypassageway) into their final configuration. Within other embodiments,the stent graft is fenestrated (e.g. FEVAR—fenestrated endovascularaortic aneurysm repair) with holes in the graft body material thatmaintain the patency of important blood vessels (or side branches). Withcertain embodiments, the stent graft has a Unique Device Identification(“UDI”) number.

Within embodiments of the invention one or more ISMs, and/or sensors maybe placed on (the luminal side or abluminal side), and/or within a stentgrafts (e.g., within the metallic struts of the stent graft orembroidered into the fabric of the stent graft). Representative examplesof sensors placed on a stent graft are provided in PCT Publication No.WO2014/100795, which is hereby incorporate by reference in its entirety.

B.1.A. Stent Grafts and Endoleaks

As noted above, stent grafts are typically utilized in a wide variety ofmedical procedures to open up and/or maintain the lumen of a bodypassageway (e.g. artery, gastrointestinal tract, urinary tract). Theyare most commonly used however for vascular procedures, e.g., in thetreatment of aortic aneurysm disease. An aortic aneurysm (AA) is adilatation of the aorta that usually results from underlying disease(typically atherosclerosis) causing weakness in the vessel wall. As theaneurysm progressively grows (dilates) in size over time, the risk of itbursting or rupturing rapidly increases; a condition which if notpromptly treated, leads to massive hemorrhage and death. Stent graftsare inserted into an aneurysm, not only to simply hold open the diseasedvessel, but also to bridge across the dilated vascular segment fromhealthy vessel to healthy vessel.

Briefly, a stent graft is inserted over a guide wire, from the femoralor iliac artery and deployed within the aneurysm, resulting inmaintenance of blood flow from an aorta of acceptable (usually normal)caliber above the aneurysm to a portion of aorta or iliac artery(s) ofacceptable (usually normal) caliber below the aneurysm. The aneurysm sacis thus excluded from the circulation. Blood within the excludedaneurysm sac thromboses and thus has no flow within it, presumablyreducing the pressure and thus its tendency to burst.

Presently available stent grafts, however, have a number of limitationssuch as endoleaks, migration, detachment, wear and durability issues,rupture, stenosis, kinking and malpositioning. For example, currentstent grafts are prone to persistent leakage of blood around the area ofthe stent graft and into the aneurysm sac (a condition known as an“endoleak”). Hence, pressure within the aneurysm sac is not reduced,stays at or near arterial pressure, and the aneurysm remains at risk forrupture. Endoleaks are among the most common and the most clinicallydangerous complications of stent graft placement and the early detectionand treatment of endoleaks remains a significant medical problem. Stentgrafts of the present invention have, within certain embodiments,pressure detecting sensors that are able to detect elevated pressurewithin the aneurysm sac and warn the patient and/or the attendingphysician that there may be a potential endoleak. Pressure sensorscontained within an ISM that is itself contained within a stent graft(e.g., within the metallic struts of the stent graft or embroidered intothe fabric of the stent graft) or attached to a stent graft canrecognize adluminal (the outer surface of the graft in contact with theblood vessel wall) pressure rising; this is suggestive that pressurewithin the aneurysm sac is becoming elevated and that the aneurysm is nolonger excluded from the circulation. Since most endoleaks areasymptomatic to the patient (rupture is often the first symptom), agradual or rapid increase in stent graft adluminal pressure (or aneurysmwall pressure) is an important early indicator that medical care shouldbe sought and that investigation into its underlying cause is warranted.Currently, there is no such continuous monitoring and early detectionsystem available to recognize endoleaks and embodiments of the presentinvention will greatly facilitate the identification and early treatmentof this potentially fatal complication of stent graft treatment.

There are 5 common types of perigraft leakage (endoleak), and correctivemeasures can vary depending upon the underlying cause. Stent grafts ofthe present invention contain, within certain embodiments, ISMscomprising one or more sensors of various types including but notlimited to fluid pressure sensors, contact sensors, position sensors,pulse pressure sensors, blood volume sensors, blood flow sensors,chemistry sensors (e.g., for blood and/or other fluids), metabolicsensors (e.g., for blood and/or other fluids), accelerometers,mechanical stress sensors, temperature sensors, and the like, which arecapable of providing information useful to the physician for determiningwhich type of endoleak might be present.

The first type of endoleak (Type I Endoleak) occurs when there is directleakage of blood around the stent graft (either proximally or distally)and into the aneurysm sac. This type of endoleak can be persistent fromthe time of insertion because of poor sealing between the stent graftand vessel wall, or can develop later because the seal is lost. Inaddition, this problem can develop due to changes in the position ororientation of the stent graft in relation to the aneurysm as theaneurysm grows, shrinks, elongates or shortens with time aftertreatment. Type I endoleaks also commonly occur if the stent graft“migrates downstream” from its initial point of placement as a result ofbeing shifted distally by the flow of blood and arterial pulsations.Representative stent grafts can have an ISM with contact and/or positionsensors implanted/affixed to the proximal end of the stent graft todetect loss of contact with the vessel wall which could be indicative ofa potential Type I endoleak. IMRs could also be located at the distalends of the stent graft (as well as within the body of the stent graft)to assist in the identification of a Type I endoleak. Stent graftsequipped with an ISM (or ISMs) having pressure and contact sensingdevices can indicate the suspected presence of an endoleak through thedetection of elevated adluminal pressure; furthermore loss of contactwith the vessel wall (as detected by the contact sensors) at theproximal and/or distal ends of the graft would suggest the presence of aType I endoleak, while loss of contact of the body of the stent graftwith the vessel wall would suggest the location, size and extent of theendoleak present in the aneurysm sac. Lastly, ISMs having positionsensors and/or accelerometers concentrated at the proximal and/or distalends of the stent graft (as well as in the body of the stent graft) candetect movement (migration) of the stent graft from its original pointof placement (a common cause of Type I Endoleaks) and also aid indetermining the size and location of the endoleak (by detectingdeformations of the stent graft wall).

As noted above, within certain embodiments of the invention specificsensors can be identified by their USI, as well as by their positionallocation within the stent graft. Hence, a more comprehensive image oranalysis of the overall function of the stent graft (and of thepatient's response to the stent graft) can be ascertained based uponknowledge of the location and activities of a group of sensorscollectively. For example, a collection of sensors, when analyzed as agroup could be utilized to ascertain the specific type of endoleak, thedegree and the location of the endoleak. In addition, the collection ofsensors could be utilized to assess a variety of other conditions,including for example, kinking or deformation of the stent graft, andstenosis of the stent graft.

The second type of perigraft leak (Type II Endoleak) can occur becausethere are side arteries extending out the treated segment of bloodvessel (typically the lumbar arteries, testicular arteries and/or theinferior mesenteric artery). Once the aneurysm is excluded by the stentgraft, flow can reverse within these blood vessels and continue to fillthe aneurysm sac around the stent graft. Representative stent grafts canhave ISMs with contact and/or position sensors (ideally an ISM would beincorporated to the proximal and distal ends of the stent graft, as wellas well potentially as within the body of the stent graft) to assist inthe identification of a Type II endoleak. Stent grafts equipped withISMs having pressure and contact sensing devices can indicate thesuspected presence of an endoleak through the detection of elevatedadluminal pressure; furthermore continued contact with the vessel wall(as detected by the contact sensors) at the proximal and/or distal endsof the graft would suggest the endoleak could be a Type II, while lossof contact of the body of the stent graft with the vessel wall wouldsuggest the location, size and extent of the endoleak present in theaneurysm sac. Lastly, ISMs having position sensors and/or accelerometersconcentrated at the proximal and distal ends of the stent graft wouldconfirm that the stent graft had not migrated from its original point ofplacement, while those in the body of the stent graft would aid indetermining the size and anatomical location of the endoleak (bydetecting deformations of the stent graft wall) which could suggest theblood vessel responsible for the Type II endoleak.

The third type of endoleak (Type III Endoleak) can occur because ofdisarticulation of the device (in the case of modular or segmenteddevices). Due to the complicated vascular anatomy, the diversity ofaneurysm shapes and the need to custom fit the stent graft to aparticular patient, many stent grafts are composed of several segmentsthat are inserted separately and constructed within aorta into theirfinal configuration. Disarticulation of the device at the junctionpoints can develop due to improper placement or deployment, or due tochanges in shape of the aneurysm as it grows, shrinks, elongates orshortens with time after treatment. Representative segmented stentgrafts can have ISMs having contact and/or position sensorsimplanted/affixed to the stent graft at the articulation points toassist in assessing the integrity of the seal between stent graftsegments. During placement of the stent graft, ISMs having complimentary(paired/matched) contact sensors on the respective articulated segmentscan confirm that a precise and accurate connection has been achievedduring construction of the device. Should a Type III endoleak develop,gaps/discontinuities between contact sensors on complimentary segmentscan be detected to ascertain both the location and extent of theendoleak present.

A fourth type of endoleak (Type IV Endoleak) occurs due to thedevelopment of holes within the graft material through which blood canleak into the aneurysm sac. Continuous pulsation of the vessel causesthe graft material to rub against the metallic stent tynes eventuallyleading to fabric wear and graft failure. Representative stent graftshave ISMs with fluid pressure sensors, contact sensors, positionsensors, pulse pressure sensors, blood volume sensors, blood flowsensors, chemistry sensors (e.g., for blood and/or other fluids),metabolic sensors (e.g., for blood and/or other fluids), accelerometers,mechanical stress sensors, temperature sensors, and the like that areincorporated within the body of the stent graft (e.g., within themetallic struts of the stent graft or embroidered into the fabric of thestent graft) to assist in the identification of a Type IV endoleak.Should a defect develop in the graft material, the embedded ISM sensorswill aid in determining the size and location of the endoleak bydetecting deformations and defects of the stent graft wall. In extremecases, stent graft wall defects can lead to rupture of the stent graft;a condition that can be detected early as a result of embodiments ofthis invention.

The final type of endoleak (Type V Endoleak) is a leak of unknownorigin. Representative stent grafts equipped with ISMs having fluidpressure sensors, contact sensors, position sensors, pulse pressuresensors, blood volume sensors, blood flow sensors, chemistry sensors(e.g., for blood and/or other fluids), metabolic sensors (e.g., forblood and/or other fluids), accelerometers, mechanical stress sensors,temperature sensors, and the like can indicate the suspected presence ofan endoleak through the detection of elevated adluminal pressure.Furthermore, loss of contact with the vessel wall detected by contactsensors, changes in position sensors and/or movements detected byaccelerometers can detect changes in the stent graft and assist indetermining the size and location of the endoleak (by detectingdeformations of the stent graft wall).

The integration of data from the fluid pressure sensors, contactsensors, position sensors, pulse pressure sensors, blood volume sensors,blood flow sensors, chemistry sensors (e.g., for blood and/or otherfluids), metabolic sensors (e.g., for blood and/or other fluids),accelerometers, mechanical stress sensors, temperature sensors, and thecan produce a computer reconstruction of the stent graft wall that canserve a function similar to medical “imaging” of the device (see e.g.,FIGS. 9 and 10). Stent grafts of the present invention containing ISMs,within certain embodiments, can provide sensing information to serve avariety of important clinical functions.

For example, this information is useful to the clinician during initialplacement of the stent graft to determine if it is correctly placedanatomically, if there is leakage around the graft, if stent graftsegments are correctly assembled, to detect kinking or deformation ofthe graft, to ascertain if there is uniform blood flow through thedevice—to name but a few important functions. Malpositioning of thestent graft, either at the time of placement or due to subsequentmovement/migration, is a common complication of stent graft therapy.ISM-containing stent grafts of the present embodiment can be used toconfirm proper initial placement, assembly and deployment and anyensuing disarticulation or migration. Detachment of the graft as a whole(from the artery), or detachment of individual graft segments from eachother is another problematic complication of stent graft insertion andongoing therapy. Stent grafts of the present invention have the abilityto detect movement/detachment of the entire stent graft, as well asmovement and/or detachment of individual segments, providing theclinician and patient with valuable diagnostic information. Kinking ofthe stent graft during deployment and/or as the result of subsequentmovement after placement is also a significant clinical problem if itdevelops. Stent grafts of the present invention have ISMs with positionsensors and accelerometers distributed throughout the stent graftcapable of detecting deformation and kinking of the stent graft.

In some cases, the lumen of the stent graft can become narrowed andrestrict blood flow through the graft due to external compression (suchas an endoleak), stenosis (the growth of thickened vascular tissuecalled neointimal hyperplasia on the inner surface of the stent graft),or the formation of a blot clot. Stent grafts of the present inventionhave a variety of ISM containing sensors capable of detecting anddifferentiating types of stenosis. Blood flow, fluid pressure and bloodvolume sensors located on the luminal surface are able to detect thepresence and location of a stenosis due to the increased blood flowspeed and increased blood (and pulse) pressure at the site of a stenosis(relative to normal segments of the graft). Stenosis due to externalcompression (such as the presence of an endoleak as discussed above)will be experienced as such (increased blood flow speed and increasedpressure). Stenosis due to neointimal hyperplasia or luminal clotformation will be detected as “dead spots” and/or altered readings onthe luminal surface as ISMs having blood flow sensors, blood metabolicand/or chemistry sensors (e.g., for blood and/or other fluids) willbecome covered by vascular tissue or clot and will cease to register;while ISM adluminal pressure sensors and accelerometers will not showchanges in adluminal pressure or stent graft wall deformation (as wouldoccur with an endoleak). ISMs having metabolic sensors and chemistrysensors are capable of determining the difference between stenosis(normal pH and physiologic readings) and clot (lowered pH and alteredphysiologic readings).

As mentioned, stent grafts are often placed in arteries (typically theaorta) in anatomic locations where important arterial side branchesoriginate. Of greatest importance are the renal arteries, but thelumbar, testicular, inferior mesenteric and internal iliac arteries canbe affected by an aortic aneurysm. To maintain patency of these arteries(and prevent them from being obstructed by the placement of the stentgraft), stent grafts with holes (or fenestrations) have been developedthat allow blood flow through the graft and into the arteries thatbranch out from the aorta. FEVAR (fenestrated endovascular aorticaneurysm repair) is a form stent graft design and treatment thatmaintains the patency of important blood vessels that originate from theaorta. Stent grafts of the present invention have ISMs possessing bloodflow sensors, fluid pressure sensors, pulse pressure sensors, bloodvolume sensors and/or blood chemistry and metabolic sensors at thefenestration sites to monitor blood flow through the side branches.Stent grafts of the present invention may also have ISMs having positionsensors, contact sensors and/or accelerometers at the fenestration sitesto monitor patency of the side branches (due to stenosis and/or kinking,migration and obstruction of the arterial branches by the stent graftitself).

In addition, patients requiring stent grafts often have extensivecardiovascular disease resulting in impaired cardiac and circulatoryfunction. For example, patients receiving stent grafts are at anincreased risk for myocardial infarction (heart attack), congestiveheart failure, renal failure and arrhythmias. The aorta is the largestblood vessel to originate from the heart; therefore, monitoring certainhemodynamic and metabolic parameters within the aorta can provide theclinician with very important information regarding the patient'scardiac, renal and circulatory function. Stent grafts of the presentinvention contain ISMs having fluid pressure sensors, contact sensors,position sensors, pulse pressure sensors, blood volume sensors, bloodflow sensors, chemistry sensors (e.g., for blood and/or other fluids),metabolic sensors (e.g., for blood and/or other fluids), accelerometers,mechanical stress sensors, temperature sensors, and the like, suitablefor such purposes. Representative stent grafts of the present inventioncan have ISMs with pressure sensors, pulse pressure sensors, pulsecontour sensors, blood volume sensors, blood flow sensors on and/orwithin the stent graft which can be used by one of ordinary skill in theart to calculate and monitor important physiologic parameters such ascardiac output (CO), stroke volume (SV), ejection fraction (EV),systolic blood pressure (sBP), diastolic blood pressure (dBP), meanarterial pressure (mAP), systemic vascular resistance (SVR), totalperipheral resistance (TPV) and pulse pressure (PP). For example, theFloTrac/Vigileo (Edwards Life Sciences, Irvine, Calif.) uses pulsecontour analysis to calculate stroke volume (SV) and systemic vascularresistance (SVR); the pressure recording analytical method (PRAM) isused by Most Care (Vytech, Padora, Italy) to estimate cardiac output(CO) from analysis of the arterial pressure wave profile. Changes incardiac output (CO), stroke volume (SV) and ejection fraction (EF) andcardiac index (CI) can be an important in detecting complications suchmyocardial ischemia and infarction; they can also assist the clinicianin implementation and adjusting cardiac medications and dosages. ISMshaving pulse pressure sensors, pulse contour sensors and heart ratesensors contained on and within stent grafts of the present inventioncan assist in the detection and monitoring of cardiac arrhythmias andheart rate abnormalities; they can also be used to monitor the patient'sresponse to cardiac medications that effect heart rate and rhythm.Systolic blood pressure (sBP), diastolic blood pressure (dBP), meanarterial pressure (mAP), systemic vascular resistance (SVR) and totalperipheral resistance (TPV) readings can be used by the clinician tomonitor the dosage and effect of blood pressure lowering medications andpressor (blood pressure increasing) agents.

As described above, patients requiring stent grafts often haveconcurrent medical problems related to cardiovascular disease such asrenal impairment or renal failure. The renal arteries originate from theaorta, often in close approximation to the typical location of stentgraft placement; therefore, monitoring certain hemodynamic and metabolicparameters within the aorta can provide the physician and patient withvery important “real time” information regarding ongoing renal function.Stent grafts of the present invention can contain ISMs havingcirculatory sensors (as described herein) as well as chemistry sensors(e.g., for blood and/or other fluids) and metabolic sensors (e.g., forblood and/or other fluids) suitable for monitoring kidney function.Examples of blood chemistry and metabolic sensors of utility for thisembodiment include, but are not limited to, Blood Urea Nitrogen (BUN),Creatinine (Cr) and Electrolytes (Calcium, Potassium, Phosphate, Sodium,etc.). Furthermore, combining metabolic data with hemodynamic data andurinalysis can allow the clinician to calculate the GlomerularFiltration Rate (GFR) which is a very useful measure of kidney function.This information would be of particular utility in the management ofdialysis patients to monitor the timing, effectiveness, and frequency ofdialysis therapy.

Finally, due to the numerous complications described above, there islong term uncertainty about the utility of stent graft technology as atreatment for aortic aneurysm. Although much more invasive andtraumatic, standard open surgical aneurysm repair is extremely durableand effective. Uncertainties about endovascular stent grafts includewhether they will lower the aneurysm rupture rate, rate of perigraftleak (endoleak), device migration, ability to effectively excludeaneurysms over a long term, and device rupture or disarticulation. Stentgrafts containing ISMs of the present invention, with their ability todetect and monitor many (if not all) of the aforementionedcomplications, are an important advancement of stent graft therapy as awhole.

Representative examples of sensors placed on a stent graft are providedin PCT Publication No. WO2014/100795, which is hereby incorporate byreference in its entirety).

B.1.B. Representative Embodiments of Stent Grafts and Endoleaks

Representative examples of stent grafts having ISMs are shown in FIGS. 7and 8. Briefly, FIG. 7 illustrates an abdominal aortic aneurism of thetype which may occur in patients. A stent graft has been positionedinside the aneurism to form a stent graft which is in physical contactwith a blood vessel wall proximally and distally (and “seals” orexcludes the aneurysm from the circulation). While such stent grafts arebeneficial to reduce pressure in the aneurism sac and significantlyincrease the health of the patient, sometimes difficulties occur inwhich blood gets around or through the stent graft leading to varioustypes of endoleaks. In order to monitor the health of the patient, it isdesirable to identify any one of the five types of endoleaks (discussedabove) which may occur in a stent graft. In addition, it is desirable tomonitor cardiac output, blood flow, blood volume, and variouscharacteristics of the blood internal to the stent graft.

FIG. 7 also illustrates that one or more ISMs can be positioned in, on,or within the wall of the stent graft (e.g., within the metallic strutsof the stent graft or embroidered into the fabric of the stent graft) inorder to sense various conditions of the stent graft relative to theblood vessel, the circulation, and the status of the aneurism. Althoughthe ISM (or ISMs) can be located wherever is practical (e.g., multipleISMs can be located in bands, proximally, distally, and/orcircumferentially throughout the stent), particularly importantlocations include the proximal end (and to a lesser extent the distalends) of the stent graft and the section of the graft adjacent to theaneurysm sac. For example, one or more ISMs containing one or morepressure sensors can be located at the proximal and distal ends of thestent graft, as well as within the aneurism sac in order to sense thefluid pressure at various locations along the outer wall of the stentgraft and within the aneurism sac. Additionally, the ISMs may includeone or more contact sensors and be located at the distal end of thestent graft, the proximal end of the stent graft, and various locationsalong the stent graft in contact with the aneurysm wall in order todetermine whether the stent is in physical contact with the blood vesselwall. The ISM contact sensors may be of a type of physical pressuresensors, whereas the ISM pressure sensors are fluid pressure sensors. Inaddition, one or more position markers can be placed in the ISM andlocated to determine whether or not the ISM (and hence the stent graft)has moved relative to the blood vessel wall, since movement of the stentgraft is one of the conditions which causes endoleak and failure.

Within various embodiments the ISMs may be powered by one or morebatteries that is located on the outside of the stent graft (e.g.positioned such that it would be located within a site of an aneurysm.Similarly, other components of an ISM may likewise be located on a stentgraft such that, once deployed, they would be located within the site ofan aneurysm.

An ISM with sensors which are in contact with the inner (luminal) wallof the stent graft can both monitor the integrity of the stent graft andalso the properties of the blood flowing through the stent graft.Accordingly, the ISM sensors on the luminal surface of the stent graftmay include a pulse analyzer to determine the pulse properties of thepatient. It may also include a plurality of blood pressure sensors tosense the blood pressure of the patient. It may include both blood flowand blood volume detectors to calculate the cardiac output of thepatient. In addition, the stent graft provides an excellent location inorder to determine various blood properties, such as the pH, the glucoselevel, the oxygen content, the cholesterol level, and other propertiesof the arterial blood as it flows by. Thus, a variety of differentluminal sensors in an ISM can be utilized to sense for both theintegrity of the stent graft as well as the properties of the bloodflowing through the stent graft.

The ISM sensors used can also include accelerometers and motion sensorsto detect movement of the stent graft due to heart beats, migration orother physical changes. Changes in the position of the accelerometersand/or motion sensors over time can be used as a measurement of changesin the position of the stent graft and/or vascular wall over time. Suchpositional changes can be used as a surrogate marker of vascular andstent graft anatomy—i.e. they can form an “image’ of the stent graftand/or vascular wall to provide information on the size, shape andlocation of endoleaks, kinking of the stent graft, disarticulation of asegmented stent graft, stenosis with the stent graft, clot formation,and/or stent graft movement/migration.

For example, as shown in FIG. 8 is an enlargement of the proximal end ofthe stent graft showing the location of an ISM containing varioussensors which can perform sensing functions for both for the integrityof the stent graft and the blood properties of the patient. Morespecifically, FIG. 8A shows development of an endoleak, which eventuallybecomes more complete (FIG. 8B). As shown in the blown-up images (FIGS.8C and 8D), an ISM located in the stent graft wall adjacent to theaneurysm sac will possess sensors that will be moved from their typical(original) specified position, to a different position, as a result ofthe endoleak. The movement, rate of movement, pressure, and othermetrics of measurement (depending upon the type of sensors contained inthe ISM) can be interrogated at a single time point, as well as over atime course to follow the progression of the endoleak (and thesuccess/failure of treatment attempts to correct it). Moreover, thethree-dimensional spacial deformation of the stent graft (andfour-dimensional if time is also considered), may be determined basedupon the movement, pressure, and other metrics of the ISM sensors andused to provide sizing and anatomical location of the endoleak.

The, collection of data from the ISM sensors can also be utilized toensure proper placement of the stent graft (e.g., that no leaks arepresent at the time of placement), complete articulation of the stentgraft, full deployment (expansion) of the stent graft, and that thestent graft is appropriately positioned (e.g., relative to the aneurysmand arterial branches of the aorta).

B.2. Stents

Within one embodiment of the invention, stents are provided having oneor more ISMs as described herein. Briefly, “stent” refers to a medicaldevice that can be utilized to hold open body structures and/orpassageways, and can be utilized to treat and/or prevent a wide varietyof diseases and/or conditions resulting from lumen narrowing orobstruction; whether due to an injury or external compression of thevessel wall (a benign or malignant tumor, abscess, cyst), a diseaseprocess occurring within the vessel wall (e.g., cancer, atherosclerosis,inflammation, scarring or stenosis), a disease processes occurring onthe surface (or in the lumen) of the vessel wall (thrombus,atherosclerosis, restenosis, tumor growth, inflammation and scarring,biliary and urinary “stones”, mucous impaction, etc.), and/or anoperation or other medical intervention causing damage to the vessel.

Stents can be used in a wide variety of variety of tubular bodypassageways to preserve the normal movement of luminal materials (blood,digestive contents, digestive enzymes and bile, air, urine, reproductivematerials) through them, including for example, vascular structures(e.g., coronary, carotid, cerebral, vertebral, iliac, femoral,popliteal, tibial, mesenteric, pulmonary, and other branches of thesearteries; large veins such as the superior and inferior vena cava andveins of the neck, upper and lower extremities), gastrointestinalstructures (e.g., esophagus, duodenum, small intestine, colon, biliarytract and pancreatic ducts), pulmonary structures (e.g., to hold openthe trachea, bronchi, or bronchioles), urinary system structures(collecting system, ureters, urethra), female and male reproductivesystem structures (e.g., to maintain patency of the fallopian tubes,prostatic urethra), sinus structures in the head and skull (maxillarysinus, frontal sinus, lacrimal duct), and inner ear structures(tympanostomy tubes).

Typically, stents are composed of metallic or polymeric components, andhave a unitary structure, or multiple components (e.g., a bifurcatedstent system). Stents may be non-degradable, partially degradable, orfully degradable. In addition, stents may be coated with one or moredifferent compositions, including both polymers and drugs (includingbiologics and stem cells). Representative examples of stents includethose disclosed in U.S. Pat. Nos. 6,852,153, 7,942,923, 7,753,947,7,879,082, and 8,287,588, as well as various publications (see, e.g.,“Open Stent Design: Design and analysis of self expanding cardiovascularstents”, by Craig S. Bonsignore, CreateSpace Independent PublishingPlatform, November 2012, and “Coronary Stents” by Sigwart and Frank(eds.), Springer, 2012)

Within preferred embodiments the stents of the present invention have aUnique Device Identification (“UDI”) number, and each of the sensors ofthe ISM located within the stent have a Unique Sensor Identification(“USI”).

In addition, within various embodiments of the invention one or moreISMs, and/or sensors may be placed on (the luminal side or abluminalside), and/or within a stent (e.g., within the metallic struts of thestent or embroidered into the fabric of a “covered” stent).Representative examples of sensors placed on a stent are provided in PCTApplication No. PCT/US2014/028323, which is hereby incorporate byreference in its entirety).

B.2.A. Stents and their Use

As noted above, stents are used to open up and maintain the lumen of adiseased body passageway (e.g. artery, gastrointestinal tract, urinarytract), but have found their greatest utility in the management ofvascular disease. Briefly, a stent is inserted into body a lumen tophysically hold open structures and/or passageways (typically tubularorgan structures such as blood vessels, the gastrointestinal tract, theurinary tract, the sinuses of the skull, the respiratory tract, or themale and female reproductive tracts) which have become blocked orpartially obstructed thereby reducing or eliminating the movement ofmaterials (typically fluids, solids or air) through them. The stent isusually placed percutaneously (e.g. vascular stents are often insertedinto the vasculature via the femoral artery in the groin or the radialartery in the arm and then maneuvered through the blood stream underradiological guidance until they reach the diseased blood vessel) or viainsertion through a natural orifice (e.g. the mouth, nose, anus,urethra) and placed under direct vision (endoscopy) into the affectedorgan (lungs, GI tract, urinary tract). Most often the stent isdelivered to the deployment site in a compressed form and then expandedinto place (often by inflating a balloon with the stent or through theuse of “self-expanding” stents) to open the organ lumen back up to itsoriginal size and shape. The symptoms of blockage or obstruction (e.g.chest pain, claudication, neurological deficit, dysphagia, bowelobstruction, jaundice, difficulty breathing, infertility, urinaryobstruction, sinus pain) depend upon the organ affected and restorationof normal anatomy and lumen function is the goal of stent treatment.Stent failure can be due to a multitude of causes but includes thingssuch improper placement, improper sizing, incomplete opening ordeployment of the stent, tissue ingrowth into the stent lumen(restenosis, tumor cell growth, inflammation), luminal obstruction(clot, biliary stone, kidney stone), stent fracture, stent kinking andstent migration. Stents containing ISM sensors able to assist thephysician in their proper placement and deployment, and stents capableof ongoing monitoring to detect evidence of partial and/or completeobstruction, would have significant benefits over existing devices.

Within various embodiments an ISM containing sensors can be positionedon/in the stent in a location where the sensors are exposed to the bloodflowing through the stent (on the luminal surface of the stent). A widevariety of sensors can be placed in an ISM on the luminal wall of thestent, within the stent, and/or, on the outer (adluminal) wall of thestent (for example, part of the stent strut itself can be composed of anISM such that the sensors are in contact with all aspects—luminal,internal, adluminal—of the stent). Representative sensors that can beutilized within one or more ISMs on/in a stent include fluid pressuresensors, contact sensors, position sensors, pulse pressure sensors,blood volume sensors, blood flow sensors, blood chemistry sensors, blood(and tissue) metabolic sensors, accelerometers, mechanical stresssensors, vibration sensors and temperature sensors.

Within various embodiments, vascular stents (coronary, peripheral andcerebral) of the present invention can have one or more ISMs withvariety of sensors capable of detecting and differentiating types ofnormal vascular healing versus stenosis, restenosis, and/or thrombosis.For example, as generally shown in FIG. 11, an ISM can be containedwithin or on the strut or tynes of a vascular stent and contain sensorsthat detect blood flow, fluid pressure and blood volume on the luminalsurface such that they are able to detect the presence and location of astenosis due to the increased blood flow speed and increased blood (andpulse) pressure at the site of a stenosis (relative to normalpressures). Stenosis due to neointimal hyperplasia or clot formation canbe detected as “dead spots” and/or altered readings on the luminalsurface as an ISM having blood flow sensors, blood metabolic and/orblood chemistry sensors that become covered by vascular tissue or clotwill no longer obtain readings; however, “upstream” sensors will showincreased pressure and decreased flow rates, while sensors “downstream”from the obstruction will show decreased pressure and increased flowrates (a “jet” effect). An ISM having metabolic sensors and chemistrysensors are capable of determining the difference between stenosis(normal pH and physiologic readings) and clot (lowered pH and alteredphysiologic readings). Lastly, complete coverage of the luminal surfaceof the stent in the absence of altered pressure, blood flow rates, stentdeformation and metabolic/chemistry readings is suggestive of normalhealing; that the stent has become endothelialized (covered with thecells that line the body's blood vessels). This indicator of healthy andcomplete incorporation of the stent within the blood vessel wall (i.e.the stent is no longer exposed to the elements of the bloodstream) hasan important clinical consequence—it alerts the clinician that it may bepossible to discontinue the patient's (costly and dangerous)anticoagulant therapy since the risk of subacute and delayed thrombosisis now markedly reduced. In the case of biodegradable stents, completecoverage of the luminal surface of the stent and incorporation of itinto the vessel wall means that dissolution of the stent is now safe(i.e. stent fragments will not be released into the blood stream).

In addition, subjects requiring stents often have extensivecardiovascular disease resulting in impaired cardiac and systemiccirculatory function. For example, subjects receiving stents are at anincreased risk for myocardial infarction (heart attack), cerebralvascular accidents (stroke), congestive heart failure, renal failure andarrhythmias. The coronary arteries are critical to the functioning ofthe heart, and hence, monitoring certain hemodynamic and metabolicparameters within these arteries can provide the clinician with veryimportant information regarding the subject's cardiac, renal andcirculatory function. Coronary stents of the present invention cancontain one or more ISMs with fluid pressure sensors, contact sensors,position sensors, pulse pressure sensors, blood volume sensors, bloodflow sensors, blood chemistry sensors, blood metabolic sensors,accelerometers, mechanical stress sensors, temperature sensors, and thelike, suitable for such purposes. Representative stents of the presentinvention can be utilized by one of ordinary skill in the art tocalculate and monitor important physiologic parameters such as cardiacoutput (CO), stroke volume (SV), ejection fraction (EV), systolic bloodpressure (sBP), diastolic blood pressure (dBP), mean arterial pressure(mAP), systemic vascular resistance (SVR), total peripheral resistance(TPV) and pulse pressure (PP). For example, the FloTrac/Vigileo (EdwardsLife Sciences, Irvine, Calif.) uses pulse contour analysis to calculatestroke volume (SV) and systemic vascular resistance (SVR); the pressurerecording analytical method (PRAM) is used by Most Care (Vytech, Padora,Italy) to estimate cardiac output (CO) from analysis of the arterialpressure wave profile. Changes in cardiac output (CO), stroke volume(SV) and ejection fraction (EF) and cardiac index (CI) can be animportant in detecting complications such myocardial ischemia andinfarction; they can also assist the clinician in implementation andadjusting cardiac medications and dosages. ISMs with pulse pressuresensors, pulse contour sensors and heart rate sensors contained on andwithin stents of the present invention can assist in the detection andmonitoring of cardiac arrhythmias and heart rate abnormalities; they toocan be used to monitor the subject's response to cardiac medicationsthat effect heart rate and rhythm. Systolic blood pressure (sBP),diastolic blood pressure (dBP), mean arterial pressure (mAP), systemicvascular resistance (SVR) and total peripheral resistance (TPV) readingscan be used by the clinician to monitor the dosage and effect of bloodpressure lowering medications and pressor (blood pressure increasing)agents. It is obvious that peripheral and cerebral vascular stentsimplanted in other arteries (renal, iliac, femoral, carotid, etc.) arecapable of monitoring virtually all of the above cardiac/vascularparameters as well.

Vascular stents of the present invention can contain ISMs withcirculatory sensors (as described herein) as well as blood chemistrysensors and blood metabolic sensors suitable for monitoring kidneyfunction. Examples of blood chemistry and metabolic sensors of utilityfor this embodiment include, but are not limited to, Blood Urea Nitrogen(BUN), Creatinine (Cr) and Electrolytes (Calcium, Potassium, Phosphate,Sodium, etc.). Furthermore, combining metabolic data with hemodynamicdata and urinalysis can allow the clinician to calculate the GlomerularFiltration Rate (GFR) which is a very useful measure of kidney function.This information would be of particular utility in the management ofdialysis subjects to monitor the timing, effectiveness, and frequency ofdialysis therapy.

Within one embodiment of the invention the stent may also comprise anISM with one or more temperature sensors. These sensors may be utilizedto track both the discrete temperature of the blood, vessel wall andsurrounding environment, but the change of temperature overtime. Suchchange in temperature may be utilize to diagnose a possible developinginfection (or other disease or condition), and allow a physician orcare-giver to treat the infection (or other disease or condition) priorto a full onset

B.2.B. Stents with Sensors Located within the Stent

As noted above, within various aspects of the invention ISMs withsensors as described herein can be contained within the stent, includingfor example, within the tines of a stent, or within holes in the strutsof the stent, or within the struts themselves. As utilized herein,“holes” should be understood to include openings that run entirelythrough a stent, as well as cavities, depressions, wells, or otheropenings or partial openings which permit insertion of a sensor withinthe stent. Representative examples of stents include those describedwithin U.S. Pat. Nos. 7,208,010, and 7,179,289.

Within yet other embodiments, an ISM is designed to be placed, in,within, or on a stent, and one or more individual sensors whichcommunicate with the ISM placed in, within, or on the stent.

B.2.C. Stent Placement, Deployment and Connections

Stents of the present invention, within certain embodiments, can providesensing information to serve a variety of important clinical functions.It is widely accepted that the greater the amount of trauma experiencedby the vessel wall during stent placement and deployment, the higher theprobability that the stent will ultimately become obstructed (often dueto restenosis). Causes of vessel trauma during placement includeinaccurate sizing (stents too large for the vessel), difficult placementand deployment (requiring extensive manipulation to place the stent),long lesions, overlapping stents, over-inflation of the balloon orover-expansion of the stent, complicated lesions (including stenting atbranch points) and placing stents in tortuous vessels. Accurateplacement, sizing, deployment, and full expansion of stents continues tobe a challenge, particularly in the vasculature, where primarilyindirect visualization techniques, such as angiography, are used forstent positioning; angiography (radio-opaque dye running through thebloodstream) shows only the vascular luminal anatomy and gives noinformation about the vessel wall anatomy (which is often the criticaldiseased segment being treated) and only limited information about thestent itself. “Real Time” sensing information from the stent containingan ISM is useful to the clinician during placement of the stent todetermine: if it is correctly implanted anatomically, if the stent isappropriately sized for the vessel in which it is placed, if it iscompletely opened (deployed) during balloon expansion (or duringself-expansion), if it exerts too much (or too little) pressure againstthe vessel wall, if stent segments are correctly assembled, if there isan optimal amount of overlap between adjacent stents, if there iskinking or deformation of the stent, if there is cracking or fracturingof the stent, and if there is uniform flow through the device—to namebut a few important functions. Stents of the present invention can allowthe operating physician to monitor many valuable parameters that canlead to better and less traumatic stent placement and deployment.

Improper sizing of the stent relative to the vessel wall in which it isplaced can significantly increase the risk of failure (particularly dueto restenosis); stents with ISM sensors able to detect the amount,presence and/or absence of pressure and contact with the vessel wall canassist in matching the stent size and degree of expansion (deployment)to that of the vessel wall. Incomplete opening of all, or parts of thestent (known as “incomplete malaposition”—areas where the stent is notin full contact with the vessel wall and it projects into the arteriallumen), increases the risk of subsequent clotting (thrombosis) and stentfailure. ISM position sensors, contact sensors and accelerometerscontained within the stent can be used to identify and correct areas ofincomplete opening (deployment) during stent insertion and furthermorecan confirm that the stent has “locked” into the fully opened position.Improper positioning (malapositioning) of the stent, either at the timeof placement or due to subsequent movement/migration, is also a commoncomplication of stent therapy. ISM sensor-containing stents of thepresent invention can be used to confirm proper initial placement andany ensuing migration or relocation within the vessel. Movement of thestent as a whole, or detachment of individual stent segments from eachother is another problematic complication of stent insertion and ongoingtherapy. Stents of the present invention have the ability to detectmovement/detachment of the entire stent, as well as movement and/ordetachment of individual segments (or fragments), providing theclinician and patient with valuable diagnostic information. Kinking ofthe stent during deployment and/or as the result of subsequent movementafter placement is also a significant clinical problem if it develops.Stents of the present invention have ISM components containing positionsensors and accelerometers distributed capable of detecting deformationand kinking of the stent. Stent cracking and fracture can be a problemwith all stents, but particularly in peripheral stents of the lower limb(due to movement of the limb or bending of the stent across the kneejoint), as well as in polymeric degradable stents (coronary, peripheraland non-vascular) that can become fragile during the polymericdegradation process. ISMs having vibration sensors, position sensors,location sensors and accelerometers located within the stent devicecould alert the clinician and the patient to the development of thiscomplication prior to it developing into an acute emergency.

Within various aspects of the invention assemblies are provided whereina stent may be composed of a unitary component which is combined withanother stent, or of multiple components which need to be placed in theappropriate configuration to ensure proper utility. When the patient hasarterial disease and vessel narrowing at branching points in thevascular tree, it is often necessary to use stents (or stent components)than can be placed together in situ to match the anatomy of theobstructed segment. For example, FIG. 9 is a schematic illustration ofvarious types of multiple stent placements, wherein ISMs with contactsensors can be utilized to ensure proper placement, configuration, andattachment (overlap) of the various stent segments. FIG. 9A illustratesa site of bifurcation with stenosis occurring at multiple points in thevessel. FIG. 9B illustrates a stent with PTCA (along with ISMs andrepresentative sensors). FIG. 9C illustrates a stent plus stentdeployment (also referred to as a “reverse-T”). FIG. 9D illustrates astent plus stent deployment (referred to as “T stenting”). FIG. 9Eillustrates a stent plus stent deployment referred to as a “Crush”(along with ISMs and representative sensors). FIG. 9F illustrates astent plus stent deployment referred to as a “Y” or “V” (along with ISMsand representative sensors). FIG. 9G illustrates a stent plus stentdeployment referred to as “Kissing”. FIG. 9H illustrates a stent plusstent deployment referred to as a “Culotte” (along with ISMs andrepresentative sensors). In each case, stents containing an ISM withmultiple sensors (the “stars” in FIG. 9), such as contact sensors(potentially “matched” or complimentary for adjacent or overlappingstents) used to confirm accurate positioning and assembly;accelerometers used to corroborate anatomical location and conformation;position sensors used to monitor movement; flow sensors used to validatevascular patency; and pressure/vessel wall sensors used to verify fulldeployment and accurate vessel sizing. Taken collectively, this sensinginformation can create a 3-dimensional image of the vascular and stentanatomy and greatly improve the data available from angiography alone.This dramatically increases the chances of accurate, safe and effectivedeployment of multiple stents in complicated vascular lesions.

FIG. 10 is a schematic illustration of ISM sensors (the “stars” in FIG.10) that can be utilized to aid and or assist the placement ofoverlapping stents. Overlapping stents are used in the treatment of longlesions or tortuous lesions where a single stent is insufficient to spanthe entire length of the diseased segments. While often effective,overlapping stents are more prone to failure and the rate of failure isdirectly proportional to the degree of overlap between adjacent stents;too much overlap increases failure risk, while too little—particularlyif there is a gap between the two stents—is equally problematic. Stentscontaining ISMs with contact sensors can be used to confirm both thepresence and the extent of overlap between adjoining stents. In apreferred embodiment the ISM contact sensors between stents are“matched,” or complementary, confirming when the ideal amount of overlaphas been achieved between neighboring stents. Furthermore, ISM pressuresensors, position sensors and accelerometers can be used to confirm thatthe overlapping segments are equally deployed to ensure that there isnot a “mismatch” in lumen size in the two stents where they overlap.

B.2.D. Partially or Fully Biodegradable Stents

As noted above, stents of the present invention (including for example,vascular (e.g., coronary, carotid, cerebral, vertebral, iliac, femoraland arteries of the lower extremities), gastrointestinal (e.g.,esophageal, duodenal, colonic, biliary and pancreatic), pulmonary (e.g.,to hold open the trachea, bronchus, or bronchi), head and neck (sinus,lacrimal, tympanostomy), and genitourinary (e.g., ureteral and urethral,prostate, fallopian tube) may be comprised of one or more biodegradablepolymers. Such stents may be fully, or partially biodegradable and orresorbable. Representative examples of such stents include for exampleU.S. Patent App. Nos. 2009/0192588, 2007/0270940, and 2003/0104030, andU.S. Pat. Nos. 6,387,124, 6,869,443 and 7,044,981.

Placement of ISMs having sensors as described herein on or within abiodegradable or partially biodegradable stent (at varying depths withinthe polymer) allows a determination of degradation of the stent, as wellas, optionally, the rate of biodegradation or resorption of the stent.Hence, within one aspect of the invention methods are provided fordetermining degradation of a stent are provided, comprising the steps ofa) providing to a body passageway of a subject an assembly comprising astent and one or more ISMs having sensors, and b) detecting a change ina sensor, and thus determining degradation of the stent. Within variousembodiments the ISM has sensors capable of detecting one or morephysiological (e.g., contact, fluid flow, pressure and/or temperature)and/or locational (e.g., location within the subject) parameters. Withinfurther embodiments the step of detecting is a series of detections overtime, and optionally, the method may further comprise the step ofdetermining the rate of degradation of the stent, and/or estimating thetime for complete degradation of the stent. Within still furtherembodiments, the stent can determine luminal coverage of the device byhealing tissue and therefore confirm that the stent is embedded withinthe vessel wall (reducing or eliminating the possibility that stentfragments are released into the luminal fluids).

Within one embodiment the biodegradable stent is an esophageal,ureteral, urethral, sinus, vascular, or prostatic stent and degradationof the stent can be monitored by detecting the loss or movement of ISMsensors over a period of time.

B.2.E. Stent Coatings

Within certain embodiments of the invention the stents provided hereincan have one or more coatings on one or more surfaces of the stent.Coatings can be provided on stents for a variety of purposes. Coatingsmay be biodegradable, or non-biodegradable, or a combination of these.Typically, many coatings are polymer-based (e.g., polymers comprised ofpolyurethane, polyester, polylactic acid, polyamino acid,polytetrafluroethylene, tephlon, Gortex®), although non-polymer coatingsmay also be utilized.

Representative examples of suitable coatings include those described in,for example, U.S. Pat. Nos. 8,123,799, 8,080,051, 8,001,925, 7,553,923,and 5,779,729, all of which are incorporated by reference in theirentirety.

B.3. Prosthetic Hip Joints

Within one embodiment of the invention, prosthetic hip joints areprovided having one or more ISMs as described herein. Briefly, “hipreplacement” as that term is utilized herein, may take a variety ofdifferent forms and may involve replacement of all or portions of thepatient's hip joint with synthetic materials. In total hip replacement(THR), both the femoral head and the acetabulum are replaced. In a hemi(partial) hip arthroplasty, only the femoral head is replaced while thepatient's own acetabulum is retained. The femoral component of a hipreplacement may be a single piece with the head and stem as an integral,complete unit, or it may be constructed in several pieces, such as afemoral stem which is then coupled to a separate femoral head piece andneck section (which is often done to provide the patient with customfitting for length and/or femoral head size). The femoral component canbe cemented in place with PMMA bone cement (cemented hip) or it can befitted precisely within the medullary canal of the femur and held inplace without cement (AML—anatomic medullary locking—stem design).Similarly, the acetabular component of a THR can also be a single piececoupled to the hip socket to receive the femoral head, or be a two-piececomponent with a shell coupled to the pelvic bone and an inner linerattached to the shell. The acetabular component of a THR can be held inplace with screws and/or cement or it can be affixed without cement.

Currently, the various components may be made of the same material, forexample, all portions can be made of metal, or individual components canbe made from a variety of different materials. For example, it is commonfor the acetabular component to have a metal shell with an outer surfacecoating to facilitate bone attachment and ingrowth, and an inner liningmade from polyethylene, ultrahigh molecular weight polyethylene,ceramic, or surgical-grade stainless steel. Similarly, there may beseveral different combinations of materials used in the construction ofthe femoral head. For example, the femoral head can be composed ofmetal, usually cobalt chromium (but also stainless steel or titanium),or a ceramic material, while the femoral stem is typically metal(stainless steel, titanium, or cobalt chromium) and often possesses asurface coating to encourage incorporation of the implant within thefemur.

As utilized herein the terms “hip implant” “prosthetic hip” or “hipreplacement” or “hip replacement or portion thereof” or “medical device”should be understood, unless the specific context requires otherwise, torefer to any or all of the various components that go into making atotal hip prosthesis, including for example, the femoral stem, femoralhead, and acetabular assembly, as well as their various sub-components.“Hip replacement prosthesis” should be understood to refer to either apartial or total hip replacement prosthesis.

Within various embodiments of the invention one or more ISMs, and/orsensors may be placed on or within a hip replacement. Representativeexamples of sensors placed on a hip replacement are provided in PCTApplication No. PCT/US2014/028323, which is hereby incorporate byreference in its entirety).

B.3.A. Medical Uses of Hip Replacements

Hip replacement is carried out when the patient loses sufficient use ofthe hip so as to result in disability, loss of movement and function,impaired ambulation, and/or continuous joint pain and discomfort. Commoncauses of impaired hip function leading to total or partial hipreplacement include trauma (typically a hip fracture; often at thefemoral neck), avascular necrosis of the hip, or various types ofarthritis (such as rheumatoid arthritis or osteoarthritis). In mostpatients, the operation is successful in improving ambulation, restoringfunction and reducing pain; as a result, it is one of the most commonorthopedic procedures in the Western World.

B.3.B. Representative Embodiments of Hip Implants

Hip replacement prostheses are described in more detail in PCTApplication No. PCT/US2014/028381, which is hereby incorporated byreference in its entirety. Briefly, the prosthesis typically, iscomprised of an acetabular shell in which an acetabular liner is placed.It also includes a femoral assembly which includes two components, afemoral head and a femoral implant or femoral stem (also having afemoral neck) (see generally, FIG. 12).

One or more ISMs having sensors can be positioned within the prosthesisin order to monitor, in situ, the real-time operation of the patientactivity and the prosthesis performance. In one embodiment, an ISMhaving contact sensors can be placed within the acetabular shell. Thesesensors detect and record contact between adjacent parts, such as thebetween the acetabular shell and the pelvis and/or between theacetabular shell and the bone cement (if present) and/or between thebone cement (if present) and the pelvis, and can detect loosening of theprosthesis and its connection to the surrounding cement (if present)and/or pelvic bone. Loosening of the acetabulum is a common complicationthat occurs (typically over 8-12 years) when bone loss takes place inthe pelvic bones surrounding the acetabulum (e.g., due to a processknown as osteolysis). Erosion of the bone around the implant may becaused by material debris (metal, ceramic, and/or polyurethanefragments) generated by friction between the femoral head and acetabularcup entering the pelvic tissues surrounding the acetabulum and causinginflammation and bone loss. Other potential causes of inflammation andosteolysis are implant vibration and motion, mechanical wear and tear,lack of biocompatibility between the implant materials and thesurrounding bone, metal allergy, and lack of biocompatibility betweenthe bone cement and the surrounding bone. In addition, an ISM havingcontact sensors may indicate that the acetabular shell is positionedfurther from the pelvic bone than desired as a result of material debrisbeing built up over time and/or the presence of inflammation between theshell and the pelvic bone. An ISM having contact sensors can also beplaced within the bone cement (if present) so as to collect data on thephysical contact between the bone cement and the acetabular prosthesisand/or between the bone cement and the pelvic bone.

Within various embodiments, an ISM having contact sensors may also bepositioned at various locations on the two surfaces of the acetabularliner. The contact sensors can therefore sense the contact (and/ormovement) between the acetabular liner and the acetabular shell (thesesensors could be “paired” so as to detect shifting between theacetabular liner and shell), as well as contact between the femoral headand the acetabular liner. Similarly the ISM having contact sensors canbe positioned at various locations on the femoral head to detect contactbetween the femoral head and the acetabular liner. Thus, in theembodiment, an ISM having a variety of contact sensors are provided inorder to monitor contact between the bone and the acetabular component,and between the femoral head and the acetabular liner. Dislocation ofthe femoral head from the natural or synthetic acetabulum of aprosthetic hip is a common complication of hip replacement occurringshortly after surgery (particularly while the surrounding supportivetissues are healing from surgery); ISM sensors on the femoral headand/or acetabulum can alert the patient and the healthcare provider ifjoint dislocation has occurred. Partial or incomplete dislocation(subluxation) of the hip joint can also occur and may not be readilyevident to the patient or the physician; contact sensors on the femoralhead and/or acetabulum can determine of the joint is functioning(tracking) correctly and if subluxation (even if subclinical orasymptomatic) is occurring.

Additional (or alternative) ISMs having contact sensors can bepositioned on or within the femoral stem as well, to monitor contactbetween the femoral stem and the femur and/or contact between thefemoral stem and the surrounding bone cement (if present). An ISM havingcontact sensors on and/or within the femoral shaft can detect looseningof the prosthesis and its connection to the surrounding cement (ifpresent) and/or the femur. Loosening of the femoral shaft is a commoncomplication that occurs when (typically over 8-12 years), bone lossoccurs in the femoral canal surrounding the femoral shaft due toosteolysis. As described above, erosion of the bone around the implantmay be caused by material debris (metal, ceramic, and/or polyurethanefragments) generated by friction between the femoral head and acetabularcup entering the femoral tissues surrounding the femoral prosthesis andcausing inflammation and bone loss. Other potential causes ofinflammation and osteolysis are implant vibration and motion, mechanicalwear and tear, lack of biocompatibility between the implant materialsand the surrounding bone, metal allergy, and lack of biocompatibilitybetween the bone cement and the surrounding bone. In addition, ISMscontaining contact sensors can also be used to detect and record contactbetween connecting parts in a modular femoral prosthesis, such as thebetween the femoral head, femoral neck and/or the femoral stem. TheseISMs, can be used to insure that the connecting elements of a modularfemoral prosthesis are properly aligned and fitted.

Within other embodiments, ISMs having strain gauges can be positioned avarious places on or within a prostheses particularly the femoral stem,but also the femoral neck and the femoral head, in order to detectstrain encountered between the prosthesis and the surrounding bone. Adecrease in strain may indicate that there is bone resorbtion (loss),which could lead to loosening of the prosthesis, or fractures. Thestrain sensors provide a different data point than the contact sensors,which merely specify whether there is current contact between adjacentstructures and thus provide a good indication of whether there isabutting contact between two surfaces. However, they do not provide anindication of the strain that is present in either of the surfaces, onthe other hand, the strain sensors output data indicative of themechanical strain forces being applied across the implant which, if notcorrected, can be a harbinger of future loosening and prosthesisfailure. In addition, an ISM having strain gauges may be of the typewhich indicates the strain which is being exhibited between twosurfaces, such as between the acetabular liner and the pelvic bone orbetween the acetabular shell and the acetabular liner.

Within other embodiments an ISM is provided with accelerometers that canbe positioned at various locations in and on the femoral shaft, femoralneck and femoral head. Accelerometers provide the benefit of being ableto detect acceleration, vibration, shock, tilt, and rotation of variouscomponents. They permit the ability to measure performance of theprosthesis under various conditions and over long periods of time.

Shortly after the hip has been replaced, the leg will be mobilized, atfirst passively, then actively; shortly thereafter, the patient willbegin gradual weight bearing on the joint. The ISM accelerometers willmeasure the movement of the hip socket during movement, including duringambulation as the leg swings forward, hits the ground, plants, is liftedoff the ground, and the body is propelled forward. In addition, theaccelerometers will measure the impact of the foot hitting the groundand the effect of the force being transferred through the femur to thepelvic bones and any vibration, shock or rotation which may occur atdifferent locations in the prosthesis. As the patient continues toimprove their range of motion postoperatively, the accelerationexperienced at different locations in the prosthetic hip joint, can bemonitored. It will be expected that as the patient heals from thesurgery, activity levels will progressively increase, ambulation willimprove, steps will be more rapid (and fluid) and, in addition, greaterstride length will be achieved with each step. This may result ingreater impact every time the foot hits the ground, which can bemeasured over time (and compared to previous values) by the variousaccelerometers positioned on the femoral head, in the femoral stem,and/or in other locations on the prosthesis. Postoperative progress canbe monitored (readings compared from day-to-day, week-to-week, etc.) andthe information compiled and relayed to both the patient and theattending physician allowing rehabilitation to be followed sequentiallyand compared to expected (typical population) norms. Within certainembodiments, a wearable device interrogates the sensors on a selected orrandomized basis, and captures and/or stores the collected sensor data.This data may then be downloaded to another system or device (asdescribed in further detail below).

Within certain embodiments of the invention, the ISM is a unitaryimplantable device such as is shown in FIG. 13. For an ISM collectingmechanical data (position, motion, vibration, rotation, shock, tilt,steps), the implanted ISM sensors (accelerometers, position sensors,pedometers) have the advantage of not requiring either direct physicalcontact with the surface of the device or with patient tissues; only asecure and immobile attachment within the prosthetic joint is needed. Ina particularly preferred embodiment, the ISM containing multiplemechanical sensors (as described above) is placed within the internalcanal of the femoral stem; a location that provides more than enoughspace to insert and seal an ISM with multiple sensor functions andbattery capability. Furthermore, the motion of the stem of a total hipjoint that occurs during normal activities (such as walking) can provideopportunities to power the ISM.

The sensors used in the ISM for contact, strain and accelerometers canbe an acceptable type of those generally available and as describedherein.

Integrating the data collected by the sensors described herein (e.g.,contact sensors, position sensors, strain gauges and/or accelerometers)with simple, widely available, commercial analytical technologies suchas pedometers and global positioning satellite (GPS) capability, allowsfurther clinically important data to be collected such as, but notrestricted to: extent of patient ambulation (time, distance, steps,speed, cadence), patient activity levels (frequency of activity,duration, intensity), exercise tolerance (work, calories, power,training effect), range of motion (discussed later) and prosthesisperformance under various “real world” conditions. It is difficult tooverstate the value of this information in enabling better management ofthe patient's recovery. An attending physician (or physiotherapist,rehabilitation specialist) only observes the patient episodically duringscheduled visits; the degree of patient function at the exact moment ofexamination can be impacted by a multitude of disparate factors such as:the presence or absence of pain, the presence or absence ofinflammation, stiffness, time of day, compliance and timing ofmedication use (pain medications, anti-inflammatories), recent activityand exercise levels, patient strength, mental status, language barriers,the nature of their doctor-patient relationship, or even the patient'sability to accurately articulate their symptoms—to name just a few.Continuous monitoring or at repeated periodic intervals as a means tomanage battery life and data collection can allow the patient and thephysician to monitor progress objectively by supplying information aboutpatient function under numerous conditions and circumstances, toevaluate how performance has been affected by various interventions(pain control, exercise, physiotherapy, anti-inflammatory medication,rest, etc.), and to compare rehabilitation progress versus previousfunction and future expected function. Better therapeutic decisions andbetter patient compliance can be expected when both the doctor and thepatient have the benefit of observing the impact of various treatmentmodalities on patient rehabilitation, activity, function and overallperformance.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM on and/or within theprosthetic hip. In addition, within various embodiments of the inventionone or more sensors may be placed separate from the ISM (but still be,optionally, able to communicate with, and be controlled, by the ISM).Representative examples of sensors placed on a hip prosthesis areprovided in PCT Application No. PCT/US2014/028381, which is herebyincorporated by reference in its entirety.

B.3.C. Coatings on Hip Implants

Within certain embodiments of the invention the hip implants areprovided that can have one or more coatings on one or more surfaces ofthe prosthesis. Coatings can be provided on hip implant for a variety ofpurposes. Coatings may be biodegradable, or non-biodegradable, or acombination of these. Representative examples of coatings arepolymer-based (e.g., polymers comprised of polyurethane, polyester,polylactic acid, polyamino acid, polytetrafluroethylene, tephlon,Gortex®), although non-polymer coatings may also be utilized. Withincertain embodiments of the invention, one or more ISMs containingsensors, as described herein, may be disbursed throughout the coating(e.g., even in a random manner).

B.4. Prosthetic Knee Joints

Within one embodiment of the invention, knee replacements are providedhaving one or more ISMs as described herein. Briefly, “knee replacement”or “knee prosthesis” as that term is utilized herein, may take a varietyof different forms and may involve replacement of all (total kneereplacement) or portions (partial knee replacement) of the patient'sknee joint with synthetic materials. In total knee replacement (TKR),both the femoral side and the tibial side are replaced. In a partial, orunicompartmental, knee replacement, only one or two portions(surfaces—tibial or femoral; or compartments—medial, lateral orpatellar) of the knee are replaced.

The various components of a TKR can typically include a femoral implant,a patellar implant, and a tibial implant (which can be composed of atibial plate—with or without a stem—and a tibial liner). Currently, thevarious components can be made from a variety of different materials,including for example, polyethylene, ultrahigh molecular weightpolyethylene, ceramic, surgical-grade stainless steel, cobalt chromium,titanium, and various ceramic materials. Within certain devices, thefemoral implant (typically made of a metal such as stainless steel,titanium, or cobalt chromium) can be designed with a bone surfacecoating to encourage incorporation of the implant within the femur andthe tibial plate (and stem) can also have a surface coating to encourageincorporation into the tibia. Representative examples of the variouscomponents of a knee replacement are described in U.S. Pat. Nos.5,413,604, 5,906,643, 6,019,794 and 7,922,771.

“Bone Cement” refers to a material that can be administered between theprosthetic hardware and the surrounding bone and hardens in place whencooled (or otherwise activated); it is an agent used to secure one ormore of the components (the prosthetic femur surface, the tibialplate/stem, the patellar “button”) of the prosthesis to the appropriatebony tissue (femur, tibia, tibial medulla, patella). Bone cement isoften composed of PMMA (polymethylmethacrylate) or PMMA and MMAcopolymer blends. It should be noted that bone screws and/or othermetallic (or polymeric) securing devices can also be used to assist inanchoring the prosthetic components to the surrounding bony tissues.

The present invention provides knee prosthesis (which may include a fullor a partial implant), medical devices (e.g., a portion of a kneeimplant, and/or components or materials which are useful in the processof implanting the device), and kits (e.g., a knee prosthesis, medicaldevice, and additional necessary materials such as bone cement and anyassociated delivery devices), all of which can have one or more of theISMs provided herein. The knee prosthesis, medical devices and kits asprovided herein (including related materials such as bone cement) arepreferably sterile, non-pyrogenic, and/or suitable for use and/orimplantation into humans. However, within certain embodiments of theinvention the knee prostheses, medical devices and/or kits can be madein a non-sterilized environment (or even customized to an individualsubject), and sterilized at a later point in time.

B.4.A. Knee Prosthesis, Medical Devices and Kits and their Use

Knee replacement is carried out when the patient loses sufficient use ofthe knee so as to result in disability, loss of movement and function,impaired ambulation, and/or continuous joint pain and discomfort. Commoncauses of impaired knee function leading to total or partial kneereplacement include various types of arthritis (such as rheumatoidarthritis or osteoarthritis, and trauma (for example, previous kneeligament injuries or cartilage/meniscus tears). In most patients, theoperation is successful in improving ambulation, restoring normal dailyfunction and reducing pain; as a result, it is a very common orthopedicprocedure in the Western World.

FIG. 14 shows a total knee joint of a type known in the art, as well asa unicompartmental (medial compartment) knee replacement. FIG. 15illustrates the components and materials of a typical artificial joint(K10), including a metallic tibial plate (K5) and tibial stem (K2)(present in this Figure, although some tibial plate components do nothave stems), a polyethylene articulating surface (K7), cement used tohold the various components in place (K4), patellar “button” prosthesis(K8), and the femoral knee component (K9).

Within one embodiment of the invention an ISM may be placed within atibial extension. For example, a portion of an artificial joint as shownin FIG. 15B may be composed of a tibial plate (FIG. 15C T1) and a tibialextension (FIG. 15C T2). The tibial extension (FIG. 15D) may becomprised of various aspects, including a screw engagement (T3), a firstportion (T4) and a second portion (T5), which optionally may be ribbedto assist with bone engagement. It is also understood that the screwengagement (T3) may be configured alternatively as a press-fit cylinder,a threaded cylinder, or other means that can be accepted into a matingunit on a tibial plate to effect fixation. Within certain embodiments ofthe invention an ISM as described herein may be placed within a tibialextension (e.g., within portion T4). Within certain embodiments theextension is formed into two pieces with a joint located at the maximumouter dimension of T5. The tibial extension containing an ISM (e.g., T4a) can be sealed at a joint using glue, threads, ultrasonic weld, or anycombination of the foregoing. Within further embodiments, a battery(e.g., T5 a) which powers the ISM may also be placed within the body ofthe tibial extension (e.g. within portion T5). Although a standardbattery is provided in FIG. 15D T5 a merely for purposes ofillustration, the battery may also be designed to have a shape whichconforms to the ribbed segment in order to maximize the battery volumeand hence its power capacity. Such shape also provides the additionalbenefit of inhibiting rotation of the battery within the tibialextension when the joint is in motion. It is also understood that thetibial extension containing the ISM can be configured as an extensionfor any total arthroplasty joint where the extension is placed into themedullary canal of bone used to seat the arthroplasty device in thepatient. Particularly preferred ISMs for use in this aspect of theinvention can be made with flexible circuitry (e.g, as shown in FIG. 15DT4 a), and have an accelerometer, and gyroscope for measurement of themovement of the artificial joint. Additionally, ISMs suitable for useherein may include one or more of: a temperature sensor, a magnetometer,a radio transceiver, an energy harvester, a signal processor, amicrocontroller, and piezoelectric sensor.

FIG. 16 depicts another typical TKR, with a femoral component, a tibialplate, a tibial lining and a patellar button which may be attached withscrews and/or cement to the underlying bone (in FIG. 16 the tibial plateis attached to the tibia by screws and/or cement as opposed to a stemmedtibial plate as depicted in FIG. 15).

FIG. 17 illustrates a representative prosthesis having one or more ISMs(10) positioned in or on the prosthesis in order to monitor, in situ,the real-time operation of the prosthesis, levels of patient functionand activity, and the prosthesis performance acutely and over time. Notethat in a knee prosthesis containing a tibial stem (as in FIG. 15), theinner canal of the tibial stem is a preferred location for the placementof an ISM.

As an example, one or more ISMs having contact sensors can be providedfor placement or attachment on or within the tibial component (theliner, plate or stem), femoral component, and/or patellar components(“button”) of a knee prosthesis. The ISM can also be contained withinthe bone cement (if present).

Within other aspects of the invention methods are provided for imaging aknee replacement or medical device containing one or more ISMs asprovided herein, comprising the steps of (a) detecting the location ofone or more sensors within an ISM in a knee replacement or medicaldevice; and (b) visually displaying the location of said one or moresensors, such that an image of the knee replacement or medical device iscreated. Within various embodiments, the step of detecting may be doneover time, and the visual display may thus show positional movement overtime. Within certain preferred embodiments the image which is displayedis a three-dimensional image.

The imaging techniques provided herein may be utilized for a widevariety of purposes. For example, within one aspect, the imagingtechniques may be utilized during a surgical procedure in order toensure proper placement, alignment and working of the knee replacementor medical device. Within other embodiment, the imaging techniques maybe utilized post-operatively in order to examine the knee replacement ormedical device, and/or to compare operation and/or movement of thedevice over time.

Within one embodiment, a prosthetic knee containing one or more ISMsequipped with contact or pressure sensors can be used to detectloosening of the prosthesis and its connection to the surrounding cement(if present) and/or bone. For example, an ISM having contact or pressuresensors located on/in the tibial component (and/or on/in the bone cementaround the tibial component), can detect loosening of the tibialcomponent within the tibia; this can be detected acutely during surgeryand alert the surgeon that some intra-operative adjustment is required.Progressive loosening of the tibial component within the tibia over time(as compared to post-operative levels) is a common complication thatoccurs when bone loss takes place (e.g., due to a process known asosteolysis); this too can be detected by the ISM contact or pressuresensors on/in the tibial component (and/or on/in the surrounding bonecement). Furthermore, ISM contact or pressure sensors located betweensegments of the tibial component (e.g. between the tibial plate and thetibial liner) can detect abnormal movement, loosening, or wear betweencomponent segments; these sensors can be “matching” (i.e. “paired”between adjacent components) so as to also allow accurate fitting during(and after) surgical placement.

Hence, in one embodiment ISMs having contact or pressure sensors areprovided in order to monitor contact between the tibia and the tibialcomponent, between the femur and the femoral component, between thepatella and the patellar component, between the complimentary segmentsof the individual prosthetic components, and between the variousarticular surfaces present (medial and lateral tibial-femoral joint; thepatellar-femoral joint) of a multi-compartmental or uni-compartmentalprosthetic knee joint. Specifically, full or partial dislocation(subluxation) of the femoral prosthetic joint surface from the naturalor synthetic tibial joint surface (medial, lateral or both) of aprosthetic knee is a common complication of knee replacement, oftenoccurring shortly after surgery (particularly during the post-operativerecovery period when the surrounding muscles and ligaments are stillhealing from surgery). ISM contact sensors on the femoral componentarticular surface and/or tibial component articular surface can alertthe patient and the healthcare provider if joint dislocation orsubluxation has occurred. This is of particular value in the detectionof subclinical partial or incomplete dislocation (subluxation) of theknee joint which may not be readily evident to the patient or thephysician; this is of greatest concern during early mobilization andpost-operative rehabilitation efforts. Additionally, an ISM havingcontact or pressure sensors on the various knee components can determineof the joint is functioning and aligning (tracking) correctly duringmovement and activity. This is particularly true with respect to themovement of the knee cap, as accurate patellar tracking can be difficultto accurately measure clinically; accurate measurement of patellartracking, both intra-operatively and post-operatively, would bebeneficial.

In other embodiment ISMs having one or more strain gauges (or sensors)are provided, including for example, on and/or within the femoralcondyle prosthesis-bone interface, on and or within the tibialbone—metal plate (and stem if present) interface, and on or within thepatellar prosthesis (patellar “button”)—patellar bone interface. In someembodiments (and to the extent space permits), the ISM having straingauges can be contained on/within the bone cement (if present) used tosecure the prosthesis to the surrounding bone, and in still otherembodiments the strain gauges are contained on/within both theprosthetic components and the bone cement (PMMA).

Within various embodiments ISMs having strain gauges can be positionedat various locations on the tibial component to detect strainencountered between the tibial prosthesis and the surrounding tibialbone (and/or bone cement if present). Many tibial prostheses contain astem that extends into the medullary canal of the tibia to enhanceanchoring and stability. A decrease in strain in the tibial prosthesisand/or tibial bone cement may indicate that conditions are present thatcould potentially lead to bone resorbtion (loss) in all, or parts, ofthe tibial canal; bone resorbtion can lead to loosening of theprosthesis, or to tibial fracture (conversely, increased strain wouldfavour bone growth in the region). Therefore, ISMs having strain sensorscan provide an indication of the strain that is present in the tibialshaft and measure the most important mechanical strain forces beingapplied across the implant which, if mal-aligned or not corrected, havea high probability of resulting in loosening and prosthesis failure. Anincrease of strain may also indicate bone hypertrophy (growth), whichcan be a source of pain. The same dynamic exists in the interfacebetween the femoral and patellar prosthetic components (and/or bonecement) and the femur and patellar; ISMs having strain gauges of thepresent invention can be used to monitor for these purposes as well.“Real life” strain information would not just be beneficial to thedoctor and patient, who could use the data to determine the (positiveand negative) effects of various activities on prosthetic-bone health,but also to manufacturers who could use it to design better prostheses.

Similarly, in other embodiments ISMs are provided having one or moreaccelerometers that can be located throughout the implant, includingISMs having accelerometers distributed on and within the femoral condyleprosthesis, on and within the tibial plate (and stem if present) andtibial liner, and on or within the patellar prosthesis (patellar“button”). In some embodiments, the ISM having accelerometers areon/within the prosthetic components themselves (tibial, femur andpatellar segments), while in others the ISM having accelerometers arecontained on/within the bone cement (if present) used to secure theprosthesis to the surrounding bone, and in still other embodiments theaccelerometers are contained on/within both the prosthetic componentsand the bone cement (PMMA).

ISMs having accelerometers provide the benefit of being able to detectacceleration, vibration, shock, tilt, and rotation of variouscomponents. They permit the ability to measure performance of theprosthesis (K10) under various conditions and over long periods of time.

During knee replacement surgery, the prosthetic joint will be movedthrough a full range of motion and stability testing to assessprosthetic function and mobility prior to surgical closure. The ISMshaving accelerometers can provide the surgeon with accurate, numeric,quantitative range of motion data at that time; this data can becompared to expected values to assess efficacy of the implantationsurgery and can serve as a baseline value for comparison to functionalvalues obtained post-operatively. Any abnormalities in vibration(indicative of an inadequate anchoring of the prosthesis in thesurrounding bone), tilt (indicative of improper tracking and/oralignment of the tibial-femoral joint and the patellar-femoral joint),rotation (indicative of dislocation or subluxation), and/or range ofmotion can be addressed at this time and allow the surgeon to makeadjustments intra-operatively. Shortly after the knee has been replaced,the leg will be mobilized post-operatively, at first passively, thenactively; shortly after recovering from the procedure, the patient willbegin gradual weight bearing on the joint. The ISM accelerometers canmeasure the movement and tracking of the knee joint during movement,including during ambulation as the leg swings forward, hits the ground,plants, is lifted off the ground, and the body is propelled forward. Inaddition, the accelerometers can measure the impact of the foot hittingthe ground and the effect of the force being transferred through thetibia to the knee joint and any vibration, shock or rotation which mayoccur at different locations in the prosthesis. As the patient continuesto improve their range of motion postoperatively, the accelerationexperienced at different locations in the prosthetic knee joint, can bemonitored. It will be expected that as the patient heals from thesurgery, activity levels will progressively increase, ambulation willimprove and increase, steps will be more rapid (and fluid) and, inaddition, greater stride length will be achieved with each step. Theeffects of exercise and various activities can be monitored by thevarious accelerometers and can be compared to patient's subjectiveexperiences to determine which life activities are improving (orinhibiting) post-operative recovery and rehabilitation.

In another embodiment, one or more ISMs containing position sensors areprovided for inclusion or attachment throughout the implant, includingISM containing position sensors distributed on and within the femoralcondyle prosthesis, distributed on and within the tibial plate (and stemif present) and tibial liner, and distributed on within the patellarprosthesis (patellar “button”). In some embodiments, the ISM containingposition sensors are on/within the prosthetic components themselves(tibial, femur and patellar segments), while in others the positionsensors are contained on/within the bone cement (if present) used tosecure the prosthesis to the surrounding bone, and in still otherembodiments the position sensors are contained on/within both theprosthetic components and the bone cement (PMMA).

ISMs having positional sensors as described herein can be utilized toprovide accurate positional data (intra-operatively andpost-operatively) for the prosthetic knee joint, including themeasurement of flexion and extension, to enhance the accuracy of aphysical exam by providing 3 dimensional data of the implant, to detectfull and partial dislocation (subluxation) of the tibial-femoral (knee)joint and/or the patella-femoral joint, and to determine proper trackingand alignment of the knee joint and the patella.

Within another embodiment ISMs can be placed in any of the polymercomponents of the medical device. Representative polymers that can,within certain embodiments, be utilized, include polyethylene, highlycrosslinked polyethylene, ultra-high molecular weight polyethylene,polyether ether ketone (“PEEK”), carbon fiber reinforced PEEK, and/orvitamin E stabilized highly crosslinked polyethylene (HXLPE) (asdescribed in greater detail below under the section entitled “MedicalPolymers”.

For an ISM collecting mechanical data (position, motion, vibration,rotation, shock, tilt, steps), the implanted ISM sensors(accelerometers, position sensors, pedometers) have the advantage of notrequiring either direct physical contact with the surface of the deviceor with patient tissues; only a secure and immobile attachment withinthe prosthetic joint is needed. In a particularly preferred embodiment,an ISM with multiple mechanical sensors (as described above) is placedwithin the internal canal of the tibial stem; a location that providesmore than enough space to insert and seal an ISM with multiple sensorfunctions and battery capability. Furthermore, the motion of the stem ofa total knee joint that occurs during normal activities (such aswalking) can provide opportunities to power the ISM.

Integrating the data collected by the sensors described herein (e.g.,contact sensors, position sensors, strain gauges and/or accelerometers)with simple, widely available, commercial analytical technologies suchas pedometers and global positioning satellite (GPS) capability, allowsfurther clinically important data to be collected such as, but notrestricted to: extent of patient ambulation (time, distance, steps,speed, cadence), patient activity levels (frequency of activity,duration, intensity), exercise tolerance (work, calories, power,training effect), range of motion and prosthesis performance undervarious “real world” conditions. Continuous monitoring or at repeatedperiodic intervals as a means to manage battery life and data collectioncan allow the patient and the physician to monitor progress objectivelyby supplying information about patient function under numerousconditions and circumstances, to evaluate how performance has beenaffected by various interventions (pain control, exercise,physiotherapy, anti-inflammatory medication, rest, etc.), and to comparerehabilitation progress versus previous function and future expectedfunction.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith, and be controlled by, the ISM). Representative examples of sensorsplaced on a knee prosthesis are provided in PCT Application No.PCT/US2014/043736, which is hereby incorporated by reference in itsentirety).

B.4.B. Use of a Knee Prosthesis, Medical Device or Kit having Sensors toMeasure Degradation or Wearing of an Implant

As noted above, within various aspects of the present invention kneeprosthesis, medical devices and kits are provided which can detect andmonitor the degradation of an implant. For example, within oneembodiment of the invention, a method is provided for degradation of aknee replacement, medical device or kit, comprising the steps of a)providing to a subject a knee replacement, medical device or kit havingone or more ISMs containing sensors as described herein, and b)detecting a change in an ISM sensor, and thus determining degradation ofthe knee replacement, medical device or kit. Within various embodimentsthe ISM sensor(s) can detect one or more physiological and/or locationalparameters. Within another embodiment, the ISM sensor(s) can detectcontact, fluid flow, pressure and/or temperature. Within yet anotherembodiment the ISM sensors can detect a location within the subject.

When a knee prosthesis degrades or is damaged, ISM sensors can detect achange so that a determination of damage and/or degradation can be made.For example, a sensor that was previously embedded within a polymerportion of a device, upon degradation may be exposed to fluid forces,and pressures where none existed before. Hence, within preferredembodiments of the invention degradation can be detected over a periodof time.

B.5. Medical Tubes

Within yet another embodiment of the invention medical tubes areprovided having one or more ISMs as described herein. Briefly, a“medical tube” refers to a generally cylindrical, closed, water-tightbody, and as utilized herein, can be used in a wide variety of medicalprocedures (e.g., the tubes are generally sterile, non-pyrogenic, and/orsuitable for use and/or implantation into humans). For example, tubescan be utilized to: 1) bypass an obstruction (e.g., in the case ofCoronary Artery Bypass Grafts, or “CABG” and peripheral bypass grafts)or open up an obstruction (balloon dilation catheters, angioplastyballoons); 2) to relieve pressure (e.g., shunts, drainage tubes anddrainage catheters, urinary catheters); 3) to restore or supportanatomical structures (e.g., endotracheal tubes, tracheostomy tubes, andfeeding tubes); and 4) for access (e.g., CVC catheters, peritoneal andhemodialysis catheters). Representative examples of tubes includecatheters (as discussed in more detail below), auditory or Eustachiantubes, drainage tubes, tracheotomy tubes (e.g., Durham's tube),endobronchial tubes, endotracheal tubes, esophageal tubes, feeding tubes(e.g., nasogastric or NG tubes), stomach tubes, rectal tubes, colostomytubes, and a wide variety of vascular grafts (e.g., bypass grafts).

Tubes may be composed of synthetic materials (e.g., silicone,polyurethane and rubber), composed of non-synthetic components (e.g.,harvested vein and artery grafts for bypass), or some combination ofthese [e.g., artificial blood vessels having a synthetic polymerscaffold, and naturally occurring cells (e.g., fibroblasts) whichproduce matrix materials for the vessel (e.g., collagen)].

“Catheter” as that term is utilized herein, refers to a thin tube thatis commonly used for a wide variety of medical conditions, and in a widevariety of medical procedures. Typically, they are inserted into a bodycavity, lumen, duct, or vessel. Catheters are often inserted into thebody by first advancing a flexible, metallic guidewire to the desiredanatomical location; the catheter is then placed over the guidewire andmaneuvered into position and the guidewire is then removed. In thismanner they can, depending on the indication or procedure, allow fordrainage, administration of fluids (e.g., saline solutions, drugs,etc.), provide access for various medical or surgical instruments,and/or of themselves be utilized to perform a wide variety of surgicalprocedures (such as balloon catheters used to dilate an obstructed bodypassageway). Catheters may be used either temporarily, or for extendedperiods of time (even permanently), and may have one, two, three, ormore lumens or channels.

Catheters may be composed of a wide variety of materials (including forexample metals such as nitinol), although most are made from polymers.Catheters may be made of either biodegradable or non-biodegradablepolymers (or combinations of these). Typical polymers that are used inthe construction of catheters include silicone, nylon, polyurethane, andpolyethylene terephthalate. As will be readily evident given thedisclosure provided herein, the catheter can be designed suitable to theintended use, and may be designed in a wide variety of forms and shapes(see e.g., FIG. 18 for an example of a balloon-based catheter having anISM with various sensors).

Catheters can be utilized for a wide variety of clinical indications andprocedures, including for example, for 1) draining fluids or eliminatingobstructions through the placement of catheters via natural bodyorifices, such as: draining the urinary tract (e.g., the bladder orkidney) via the urethra with Foley catheters, intermittent (Robinson)catheters and ureteric catheters; accessing the GI tract through analcatheters, and suction catheters; reaching the respiratory systemthrough the nose and mouth with pulmonary catheters; entering thereproductive system via the vagina (female) or urethra (male); 2)draining bodily fluids or relieving an obstruction through a surgicallycreated access into an anatomical space or cavity; e.g., peritonealcatheters (placed in the abdominal cavity for ascites, dialysis), chesttubes (placed in the pleural space for pneumothorax, pleural effusion,chylothorax, infection), pericardial drainage tubes (in the heart), CNSdrainage catheters or shunts (placed in the cerebrospinal fluid forhydrocephalus, infection, inflammation, obstruction); 3) drainagecatheters which are surgically placed percutaneously or intraoperativelyto drain collections of sterile fluid or abscesses elsewhere [can beplaced virtually anywhere, including the thorax (heart, lungs), abdomen(liver, biliary drainage catheters), knees, hips, urinary tract(ureters, kidneys, prostate, bladder), reproductive tract (uterus,fallopian tubes), GI tract (anal fistulas, other fistulas, abcesses,stomas, colostomies), soft tissues (abscesses, seromas, compartmentsyndromes) to name a few]; 4) intervenous catheters [e.g. peripherali.v.'s, central venous catheters (CVCs), peripherally-inserted centralvenous catheters (PICCs), arterial (e.g. hemodialysis access grafts andcatheters, arterial catheters), and peritoneal (e.g. peritoneal dialysiscatheters, peritoneal catheters) catheters that are placed for theadministration of fluids (e.g., intravenous administration of fluids,medication, direct administration of a desired substance (e.g., a drug)to a desired location), access, dialysis or nutrition (nasogastrictubes, feeding tubes, total parental nutrition tubes, gastric tubes); 5)catheters placed for the implementation of a medical or surgicalprocedure or device [e.g., coronary angioplasty, peripheral angioplasty,angiography, dilation of an artery and/or placement of a stent, balloonseptostomy, balloon sinuplasty, catheter-based ablation, balloondilation catheters (esophageal, biliary, tracheal, bronchial, urethral,etc.)]; and 6) catheters placed for the direct measurement of abiological function or value (e.g., arterial or venous blood pressure,cardiac function, and intracranial pressure).

Commonly available catheters include Foley-catheters for the drainage ofurine, ureteral catheters, central venous catheters (CVCs, PICCs, ports)for the administration of drugs and fluids, and Swan-Ganz cathetersutilized principally for diagnostic purposes in the pulmonary artery.Representative examples of catheters are described in U.S. Pat. Nos.8,491,569, 8,469,989, 8,460,333, 8,359,082, 8,246,568, 8,285,362,8,257,420, 8,317,713, 8,328,829, 8,262,653, 6,966,914, 5,989,213,5,509,897, 4,772,268, and U.S. Publication Nos. 2012/0310158,2012/0283641, 2012/0239032, 2012/0253276, all of which are incorporatedby reference in their entirety. Within one limited embodiment of theinvention a balloon catheter which is utilized to deploy a stent or atstent graft can be optionally excluded, to the extent said exclusion isspecifically stated or claimed.

Representative examples of intravascular catheters and balloon dilationcatheters (including drug delivery catheters and balloon catheters aredescribed in U.S. Pat. Nos. 5,180,366; 5,171,217; 5,049,132; 5,021,044;6,592,568; 5,304,121; 5,295,962; 5,286,254; 5,254,089; 5,112,305,5,318,531, 5,336,178, 5,279,565, 5,364,356, 5,772,629, 5,810,767,5,941,868, 5,362,309, 5,318,014, 5,315,998, 5,304,120, 5,282,785,5,267,985, 5,087,244, 5,860,954, 5,843,033, 5,254,089, 5,681,281,5,746,716, 6,544,221, 6,527,739, 6,605,056, 6,190,356, 5,279,546,5236424, 5,226,888; 5,181,911, 4,824,436, 4,636,195, 5,087,244,6,623,452, 5,397,307, 4,636,195, 4,994,033, 5,362,309 and 6,623,444;U.S. patent application Publication Nos. 2002/0138036, 2002/0068869,2005/0186243; and PCT Publication Nos. WO 01/15771; WO 93/08866, WO92/11890, WO 92/11895, WO 94/05361; WO 96/04955 and WO 96/22111, all ofwhich are incorporated by reference in their entirety.

“Guidewire” refers to a medical device which is utilized to positionanother medical device (e.g., an intravenous catheter, endotrachealtube, central venous line, balloon catheter, or gastric feeding tube),or to localize a tumor (e.g., during a breast biopsy). Representativeexamples of guidewires are described in U.S. Pat. Nos. 4,787,884,5,911,734, 5,910,154, 6,676,682, 6,936,065, 6,964,673, and 7,691,123 andU.S. Publication Nos. 2006/0100694, and 2007/0027522, all of which areincorporated by reference in their entirety.

B.5.A. Catheters, Tubes and their Use

B.5.A.1. Balloon Catheters and their Use

As noted above, within various embodiments of the invention, ballooncatheters (and their associated medical devices, e.g., stents and/orguidewires), are provided with one or more ISMs having one or more ofthe sensors described herein. For example, FIG. 18 illustrates a ballooncatheter having one or more ISMs containing a variety of sensorspositioned in or on the balloon catheter (and/or potentially theguidewire) in order to monitor, in situ, the real-time operation of thecatheter, the inflation and deflation of the balloon, the forces exertedby the balloon against adjacent tissues or devices (e.g. stents), flowlevels through and around the balloon, and the catheter performanceacutely and over time. The ISM containing sensors may be positionedinside the balloon catheter, within the walls of the balloon catheter,or on the outer surface of the balloon catheter. While in certainembodiments, ISMs containing contact sensors, pressure sensors, andpositions sensors can be utilized as shown in FIG. 18, a wide variety ofother sensors can also be used within the ISM that is placed in, on, orwithin the balloon catheter, including for example, fluid pressuresensors, accelerometers, vibration sensors, pulse sensors, liquid (e.g.,blood) volume sensors, liquid (e.g., blood) flow sensors, liquid (e.g.,blood) chemistry sensors, liquid (e.g., blood) metabolic sensors,mechanical stress sensors, and temperature sensors.

For example, balloon catheters containing an ISM can be inserted via aguidewire into a stenosed artery (such as a coronary artery orperipheral artery). ISMs having contact sensors able to monitor thesurface of the balloon can be utilized to measure contact with thevessel wall during inflation, deployment and deflation. Specifically,the balloon is expanded, thereby expanding the artery (coronary arteryor peripheral artery); ISMs having pressure sensors can monitor pressurein the balloon, and the pressure which is exerted against the vascularwall. Within preferred embodiments the pressure is monitored and, ifneeded, adjusted in order to prevent injury to the vascular wall due toexcessive pressure. The drop in pressure during deflation of the ballooncan also be monitored to confirm that it is safe to withdraw the ballooncatheter from the treated vascular lesion. Similarly, ISMs containingcontact sensors can be used to monitor contact of the balloon with thevessel wall during balloon deflation to confirm that it is safe towithdraw the balloon catheter from the treated vascular lesion. ISMscontaining position sensors can be utilized in balloon catheters andguidewires, in order to assist in placement of the balloon catheter,(and placement of a stent, if desired), and for medical imaging. The ISMposition sensors contained in or on the balloon can be utilized toprovide an image of vascular anatomy, pre- and post-inflation anatomy,confirmation of full balloon inflation and deflation, confirmation ofstent placement and confirmation of full stent expansion and deployment(if present).

In other embodiments, balloons containing ISMs with sensors can beutilized to assist the placement of a balloon-expandable stent. Forexample, FIG. 9A illustrates a site of bifurcation with stenosisoccurring at multiple points in the vessel. FIG. 9B illustrates a stentwith PTCA to open up a side branch. In this case, (potentially “matched”or complimentary) contact sensors on an ISM in the stent and the ballooncan be used to confirm accurate assembly; ISM accelerometers on thestent and the balloon can be used to confirm anatomical location andconformation; ISM position sensors on the stent and the balloon canmonitor movement; ISM flow sensors on the stent and the balloon canconfirm vascular patency; and ISM pressure/vessel wall sensors on thestent and the balloon can confirm full deployment and accurate vesselsizing. Taken collectively, this sensing information can create a3-dimensional image of the vascular and stent anatomy and physiology andgreatly improve the data available from angiography alone. Thisdramatically increases the chances of accurate, safe and effectivedeployment of multiple stents in complicated vascular lesions.

It should be readily evident given the disclosure provided herein thatthe above ISM-containing balloon catheters and associated medicaldevices containing ISM sensors can be utilized in the management ofnon-vascular disease. Balloon catheters are used to open up obstructedbody passageways and lumens in many other tissues, such as, but notrestricted to, the sinuses, respiratory tract, gastrointestinal tract,biliary tract, urinary tract and reproductive tract. While the size,shape and purpose of the balloon catheter (and associated devices) mayvary, the type, placement and role of various ISM sensors is analogousto that described above for the vascular system. In summary, a widevariety of ISMs having multiple sensor types may be placed on and/orwithin balloon catheters and associated devices (such as guidewires)described herein, in order to provide “real time” information andfeedback to a health care provider. Such ISM-containing balloons can beused by a surgeon during a surgical procedure safely and effectivelyopen up an obstructed body passageway, to confirm proper placement,verify anatomy, ensure effective dilation (and elimination of theobstruction), monitor forces exerted on surrounding tissues, follow fullballoon inflation and deflation, and to detect the strain/forcesencountered in a balloon procedure.

In this embodiment, the balloon catheters and associated devices (suchas guidewires) provided herein can contain one or more ISMs having oneor more contact sensors, strain gauge sensors, pressure sensors, fluidpressure sensors, position sensors, accelerometers, shock sensors,rotation sensors, vibration sensors, tilt sensors, pressure sensors,tissue chemistry sensors, tissue metabolic sensors, mechanical stresssensors and temperature sensors. The above ISMs may be continuouslymonitored in order to provide a ‘real-time’ data, imaging, and changesin function over the course of the procedure, and to better understandthe conditions which balloon catheters are exposed to in clinicalpractice.

B.5.A.2. Central Venous Catheters and their Use

Within other embodiments of the invention central venous catheters areprovided having at least one ISM having one or more sensors placedthereon. Briefly, central venous catheters (also referred to as “centrallines”, “CVC”s) are catheters that are most typically placed into thegreat veins of the body [usually the superior vena cava (SVC), or theinferior vena cava (IVC)] via access through the large vein of the neck[e.g., the internal jugular vein), the chest (e.g., the subclavian veinor axillary vein), or the groin (e.g., the femoral vein)] when reliable,longer term vascular access is required. However, CVCs can also beinserted peripherally (e.g., placed into the peripheral vasculaturesystem such as the veins of the arm and then advanced through the venoussystem until the tip reaches the SVC), and in this instance are commonlyreferred to as “Peripherally Inserted Central Catheters” or “PICC”s.CVCs are utilized to deliver medication and/or fluids to a subject, toobtain blood for testing, and for measuring pressure (typically at thedistal tip of the catheter).

CVCs can be ‘non-tunneled’ (i.e., fixed at the site of insertion), and‘tunneled’ (i.e., passed under the skin from the insertion site, to aseparate exit site). One type of catheter similar to a ‘tunneled’catheter is a “port”, which although similar, differs in that it is leftentirely under the skin. In this case, medications and fluids can beinjected directly through the skin into the port, or, for some types ofports, into a reservoir contained in the port. The term “Central VenousCatheter” or “CVC” used herein should be interpreted to include PICCs,Ports, Tunneled CVCs and Non-tunneled CVCs.

Common complications of central lines include pneumothorax, central lineassociated bloodstream infections (CRBSI), thrombosis, hemorrhage, andthe formation of hematomas or seromas at the insertion site.

Hence, central venous catheters of the present invention can be utilizedwhich have one or more ISMs having at least one of the sensors describedherein. For example, within one embodiment, central venous catheters ofthe present invention can have an ISM with one or more fluid flowsensors. Such ISMs can, within various embodiments be located on theinner (luminal) surfaces of the catheter the outer (adluminal or bloodcontacting) surfaces of the catheter, throughout the catheter, and/or(in a preferred embodiment) located at tip of the catheter. The ISMswith flow sensors can be utilized to measure fluid flow through thecatheter lumen. If at least one ISM with a flow sensor is locatedproximally and at least one ISM with a flow sensor is located at thetip, it is possible to determine if and where a blockage has occurred;for example from the formation of a fibrin sheath, catheter stenosis,catheter thrombosis, or catheter kinking (e.g., there would be decreasedluminal fluid flow rate prior to a narrowing and increased luminal fluidflow rate following an narrowing; there would be no fluid flow before orafter a complete obstruction). The ability to monitor flow rates wouldbe valuable in normal operation and during/after procedural attempts to“reopen” obstructed catheters.

Within other embodiments, ISMs having pressure sensors can beincorporated into a central venous catheter on the inner (luminal) wall,outer (abluminal) wall, and/or within the body of the catheter itself.Such ISMs are able to measure pressure within or exerted against thecatheter wall. Increased pressures can be suggestive of stenosis,thrombosis or kinking upstream from a narrowing or obstructing event,whereas decreased pressures would be seen downstream from a narrowingand (little or) no pressure would be seen downstream from anobstruction. Having the ability to measure pressure (proximally anddistally) throughout the catheter allows for functional monitoring ofthe central venous catheter (in normal operation and during/afterattempts to “reopen” obstructed catheters), and the capability to detectevents prior to a complication developing.

Within yet other embodiments, ISMs are provided having contact sensorswhich can be incorporated into a central venous catheter on the inner(luminal) wall, outer (abluminal) wall, and/or within the body of thecatheter itself to measure contact between the luminal and adluminalsurfaces and the surrounding environment. Sustained foreign body contacton either surface could be indicative of the formation of a fibrinsheath, thrombosis, biofilm formation or infection; sustained contact atthe tip could indicate that the catheter has become pushed up againstthe vascular wall and needs to be repositioned. In yet anotherembodiment, an ISM containing chemical sensors can be placed primarilyon the adluminal (blood contacting) surface in order to measure a widevariety of metabolic parameters, including for example: Blood Oxygencontent; Blood CO₂ content; Blood pH; Blood cholesterol; Blood lipids(HDL, LDL); Blood Glucose; Cardiac enzymes; Hepatic Enzymes; and KidneyFunction (BUN, Creatinine, etc.).

Within other embodiments, an ISM having position sensors can be placedin, on or within the catheter in order to allow imaging of the catheter,and detection of changes and/or movement over time. Position sensors onan ISM within a CVC catheter are useful during placement of the catheterto ensure advancement into the SVC, but not the right atria of theheart; post-placement, they can be used to determine if the catheter hasmigrated proximally or distally (into the right atrium) with time.

Within yet other embodiments, an ISM having chemical and/or temperaturesensors can be incorporated into a CVC such that it is blood contacting(on the adluminal surface) and can be utilized to monitor changes intemperature, which could suggest the presence of an infection or adeveloping infection.

In a particularly preferred embodiment, an ISM containing multiplesensors (flow sensor, position sensor, accelerometer, pressure sensor,contact sensors, chemical sensors, temperature sensors) is located atthe tip of the catheter such that it has both luminal and adluminalsurface exposure.

In summary, one or more ISMs containing a wide variety of sensors may beplaced on and/or within the central venous catheters described herein,in order to provide “real time” information and feedback to a healthcare provider (during placement, repositioning or “reopening”procedures), to detect proper anatomical placement, vascular anatomy,alignment, forces exerted on surrounding tissues, and to detect changesencountered during placement and subsequent manipulation orrepositioning procedures. For example, the central venous catheters(CVCs, PICCs, Ports) provided herein can have one or more ISMs havingone or more contact sensors, strain gauge sensors, pressure sensors,fluid pressure sensors, position sensors, accelerometers, shock sensors,rotation sensors, vibration sensors, tilt sensors, pressure sensors,blood chemistry sensors, blood metabolic sensors, mechanical stresssensors and temperature sensors.

B.5.A.3. Dialysis Catheters and their Use

Within other embodiments, specialized central venous catheters can beutilized in hemodialysis procedures (typically when dialysis is onlyneeded for a short period of time or as a bridge to permanent dialysisprocedures—see later). Briefly, a hemodialysis catheter (oralternatively—“acute dialysis catheter”) is a specialized CVC placedinto the central circulation that is used for exchanging blood to andfrom a hemodialysis machine. Typically, the catheter has two lumens, onefor venous flow and the other for arterial flow. The arterial lumenwithdraws blood from the patient and carries it to the hemodialysismachine, and the venous lumen returns blood to the patient (after theblood has been treated by the dialysis machine). Typically, flow ratesof dialysis catheters range from between 200 and 500 milliliters perminute. If the patient requires long term dialysis therapy, a ‘chronic’dialysis catheter can be utilized, which typically includes a cuff thatis buried beneath the skin (and which is believed to aid as a barrier toinfection). Common complications of hemodialysis catheters includefibrin sheath formation, clotting, biofilm formation, infection andkinking. Hence, hemodialysis catheters of the present invention can beutilized which have one or more of the ISMs described herein. Forexample, within one embodiment hemodialysis catheters of the presentinvention can have one or more ISMs having a blood flow sensor. SuchISMs can, within various embodiments be located on the inner (luminal)surfaces of the catheter, the outer (adluminal) surface of the catheter,and within the walls of the catheter; in a preferred embodiment, the ISMcontaining a blood flow sensor is located at the tip of the cathetersuch that it can measure flow in both the arterial and the venous lumen.They can be utilized to measure fluid flow through the catheter. Bycomparing the readings of ISM flow sensors at different locations in thehemodialysis catheter (i.e. the difference between proximal and distalreadings), a determination of blockage (and the extent of a blockage;for example from the formation of a fibrin sheath, catheter stenosis,catheter thrombosis, or catheter kinking) can be determined (e.g., therewould be decreased fluid/blood flow prior to a narrowing and increasedfluid/blood flow following an narrowing; there would be no fluid/bloodflow before or after a complete obstruction). The ability to monitorflow rates would be valuable in normal operation and during/afterprocedural attempts to “reopen” obstructed catheters. Within otherembodiments, ISMs having pressure sensors can be incorporated into ahemodialysis catheter on the inner (luminal) wall, outer (adluminal)wall, and/or within the body of the catheter itself. Such sensors areable to measure pressure within or exerted against the catheter wall.Increased pressures can be suggestive of stenosis, thrombosis or kinkingupstream from a narrowing or obstructing event, whereas decreasedpressures would be seen downstream from a narrowing and (little or) nopressure would be seen downstream from an obstruction. Having theability to measure pressure at different points in the catheter allowsfor functional monitoring of the hemodialysis catheter (in normaloperation and during/after attempts to “reopen” obstructed catheters),and the capability of detecting events prior to a complicationdeveloping.

Within yet other embodiments, ISMs having contact sensors can be placedon the luminal and adluminal surfaces of the hemodialysis catheter inorder to measure contact between the luminal and adluminal surfaces andthe surrounding environment. Sustained foreign body contact on eithersurface could be indicative of the formation of a fibrin sheath,thrombosis, biofilm formation or infection; sustained contact at the tipcould indicate that the catheter has become pushed up against thevascular wall and needs to be repositioned.

In yet another embodiment, ISMs having chemical sensors can be placedprimarily on the adluminal (blood contacting) surface in order tomeasure a wide variety of metabolic parameters, including for example:Blood Oxygen content; Blood CO₂ content; Blood pH; Blood cholesterol;Blood lipids (HDL, LDL); Blood Glucose; Cardiac enzymes; HepaticEnzymes; and Kidney Function (BUN, Creatinine, etc.). Many of theseparameters are important in the monitoring the need, effectiveness,timing and frequency of dialysis treatments and would be a greatassistance to the clinician managing a renal patient; similarlycomparing values in the arterial arm of the catheter, the venous arm ofthe catheter and the systemic circulation would also provide usefulclinical data.

Within other embodiments, ISMs having position sensors can be placed onor within the hemodialysis catheter (e.g., on both the luminal andadluminal surfaces, and within the catheter material itself) in order toallow imaging of the catheter, and detection of changes and/or movementover time. Position sensors are useful during placement of the catheterto ensure advancement into the proper anatomical location;post-placement, they can be used to determine if the catheter hasmigrated proximally or distally with time.

Within yet other embodiments ISMs having chemical and temperaturesensors can be utilized to monitor changes in temperature which could besuggestive of the presence of an existing infection, biofilm formationor a developing infection.

In a particularly preferred embodiment, an ISM containing multiplesensors (flow sensor, position sensor, accelerometer, pressure sensor,contact sensors, chemical sensors, temperature sensors) is located atthe tip of the catheter such that it has both luminal and adluminalsurface exposure to both the arterial and venous lumens of the dialysiscatheter.

In summary, one or more ISMs with a wide variety of sensors may beplaced on and/or within the hemodialysis catheters described herein, inorder to provide “real time” information and feedback to a health careprovider (or during placement or subsequent manipulation or “reopening”procedures), to detect proper placement, vascular anatomy, alignment,forces exerted on surrounding tissues, and to detect changes encounteredduring placement and subsequent manipulation or repositioningprocedures. For example, the hemodialysis catheters (acute and chronic)provided herein can have one or more ISMs having contact sensors, straingauge sensors, pressure sensors, fluid pressure sensors, positionsensors, accelerometers, shock sensors, rotation sensors, vibrationsensors, tilt sensors, pressure sensors, blood chemistry sensors, bloodmetabolic sensors, mechanical stress sensors and temperature sensors.The above sensors may be continuously monitored in order to provide a‘real-world’ activity, patency, and changes in function over time, toevaluate patient physiology, and to better manage the dialysis patient.

B.5.A.4. Drainage Catheters and their Use

Within other embodiments of the invention, drainage catheters areprovided having one or more ISMs placed thereon. Briefly, drainagecatheters are typically placed in order to drain fluid (e.g., surgicalfluids, blood, peritoneal fluids, CSF, biliary fluids, joint fluids,intestinal fluids, pus, an abscess, pleural fluids, or urine to name afew) from a body structure. In the context of urinary drainage, Foleycatheters, which are designed to drain urine from the bladder, andureteral catheters which are designed to allow flow of urine from thekidneys, are commonly utilized in a wide variety of medical procedures.Drainage catheters are typically made of polymers such as silicon orrubber, but other materials (including biodegradable polymers) can alsobe utilized. In the case of a Foley catheter, the catheter typically hastwo separated lumens, one of which allows urine to drain (typically to acollection bag), and the other has a valve which allows inflation of aballoon at the distal end of the catheter which is inflated within thebladder after insertion in order to ensure that the catheter doesn'tinadvertently fall out.

Common complications of drainage catheters include infections, kinkingof the catheter, biofilm build-up (resulting in potential obstructionand infection), breaking of the balloon (as well as overinflating orfailing to inflate the balloon) and the accumulation of obstructingforeign bodies (urinary stones, biliary stones, blood/clot, inflammatorytissue, fibrotic tissue, infectious tissue) on the luminal surface.

Hence, drainage catheters of the present invention can be utilized whichhave one or more of the ISMs described herein. For example, within oneembodiment, drainage catheters of the present invention can have one ormore ISMs having flow sensors. Such sensors can, within variousembodiments be located on the inner (luminal) surfaces, adluminalsurfaces of the catheter, throughout the catheter, and/or concentratedat the ends of the catheter. They can be utilized to measure fluid flowthrough the catheter. By comparing the readings of ISMs containing flowsensors at different points in the drainage catheter, a determination ofblockage (and the extent of a blockage; for example from the formationof a clot, stone, or catheter kinking) can be determined (e.g., therewould be decreased fluid flow prior to a narrowing and increased fluidflow following an narrowing; there would be no fluid flow before orafter a complete obstruction). The ability to monitor flow rates wouldbe valuable in normal operation and during/after procedural attempts to“reopen” obstructed drainage catheters.

Within other embodiments, ISMs having pressure sensors can beincorporated into a drainage catheter on the inner (luminal) wall, outer(adluminal) wall, and/or within the body of the catheter itself. Suchsensors are able to measure pressure within, or exerted against, thecatheter wall. Increased pressures can be suggestive of narrowing,thrombosis, foreign body obstruction, or kinking upstream from anarrowing or obstructing event, whereas decreased pressures would beseen downstream from a narrowing and (little or) no pressure would beseen downstream from an obstruction. Having the ability to measurepressure within the drainage catheter allows for functional monitoringof the catheter (in normal operation and during/after attempts to“reopen” obstructed catheters), and the capability of detecting eventsprior to a complication developing.

Within yet other embodiments, ISMS having contact sensors can be placedon and throughout the drainage catheter in order to measure contactbetween the luminal and adluminal surfaces and the surroundingenvironment. Sustained foreign body contact on either surface could beindicative of the formation of a fibrin sheath, thrombosis, stoneformation, biofilm formation or infection; sustained contact at the tipcould indicate that the catheter has become pushed up against theluminal wall (or an adjacent tissue) and needs to be repositioned.

Within other embodiments, ISMs having chemical sensors can be utilizedto measure a wide variety of physiological parameters, including forexample: 1) urinary function (e.g., measurement of nitrate, sodium,potassium, calcium and phosphate); 2) presence of cells (e.g., whitecells which may suggest an infection, and/or red cells which mayindicate trauma, stones, infections, and/or a malignancy); 3)protein/proteinuria (indicative of diabetes, kidney or liver disease,hyperthyroidism, etc.); 4) glucose (to measure diabetes); and variousother chemicals (e.g., ketones, bilirubin, urobilinogen, hemoglobin,creatinine, catecholamines, dopamine, cortisol, phenylalanine) andcharacteristics of the urine (e.g., specific gravity, osmolality, pH,presence of bacteria, and hcG); 5) the presence of bacteria (in allcases suggestive of infection).

Within other embodiments, ISMs having position sensors can be placedthroughout the drainage catheter (e.g., on both the luminal andadluminal surfaces, and within the catheter material itself) in order toallow imaging of the catheter, and detection of changes and/or movementover time. Position sensors are useful during placement of the catheterto ensure advancement into the proper anatomical location (prior toballoon inflation, if present, such as in Foley catheters);post-placement, they can be used to determine if the catheter hasmigrated proximally or distally with time.

Within yet other embodiments ISMs having chemical and/or temperaturesensors can be utilized to monitor changes in temperature, which couldsuggest the presence of an infection, biofilm formation, or a developinginfection.

In a particularly preferred embodiment, an ISM containing multiplesensors (flow sensor, position sensor, accelerometer, pressure sensor,contact sensors, chemical sensors, temperature sensors) is located atthe tip of the drainage catheter such that it has both luminal andadluminal surface exposure.

Taken collectively, ISMs having one or more of a wide variety of sensorsas described herein can be utilized to detect, measure and assess anumber of factors relevant to the function of the kidneys (and/orbladder) and any other organ in which the drainage catheter is placed(liver, pleural space, CSF, joint, etc.). Such drainage catheters canprovide “real time” information and feedback to a health care provider(or during placement or subsequent manipulation or “reopening”procedures), to detect proper placement, anatomy, alignment, forcesexerted on surrounding tissues, and to detect changes encountered duringplacement and subsequent manipulation or repositioning procedures. Forexample, the drainage catheters provided herein can one or more ISMswith one or more contact sensors, strain gauge sensors, pressuresensors, fluid pressure sensors, position sensors, accelerometers, shocksensors, rotation sensors, vibration sensors, tilt sensors, pressuresensors, chemistry sensors, metabolic sensors, mechanical stress sensorsand temperature sensors. The above sensors may be continuously monitoredin order to provide a ‘real-world’ activity, patency, and changes infunction over time, to evaluate patient physiology, and to better managethe drainage catheter patient.

B.5.A.6. Vascular Grafts and their Use

Within other embodiments of the invention, ISMs can be placed on avariety of vascular grafts. Briefly, medical grafts are hollow tubes orcylinders that are utilized to allow fluids (typically blood) to flowfrom one place to another. Medical grafts may be obtained from naturalmaterials (e.g., saphenous vein or mammary artery grafts), constructedfrom natural and/or artificial materials (e.g., bioengineered grafts orblood vessels), or constructed from entirely synthetic materials (e.g.,vascular grafts comprised of polymers such as polytetrafluoroethylene or“PTFE” or dacron). Representative examples of medical grafts aredisclosed in U.S. Pat. Nos. 5,556,426, 5,628,786, 5,641,373, 6,863,686,and 8,062,354.

Within one embodiment of the invention, one or more ISMs containingmultiple sensors (flow sensor, position sensor, accelerometer, pressuresensor, contact sensors, chemical sensors, temperature sensors) islocated at the distal end of the bypass graft (made from naturalmaterials) such that it has luminal surface exposure. For example,during Coronary Artery Bypass Grafting (or “CABG” procedures), arteriesor veins from elsewhere in the body can be grafted onto the coronaryarteries to bypass atherosclerotic narrowings and improve blood supplyto the myocardium (e.g., wherein saphenous veins are utilized forcoronary artery bypass, and a mammary artery is used for a coronaryartery bypass).

Within other embodiments of the invention, synthetic vascular grafts canbe utilized to bypass an obstruction (e.g., synthetic vascular bypassgrafts can be utilized to bypass an obstruction in the lower limb).Hence, grafts which have ISMs of the present invention have a widevariety of utilities. For example, within one embodiment, grafts of thepresent invention can have ISMs with one or more blood flow sensors.Such ISMs containing blood flow sensors can, within various embodimentsbe located on the inner (luminal) surfaces of the graft, on the outer(adluminal) surfaces of the graft, throughout the graft (e.g., woveninto the fabric of a synthetic graft, or incorporated into the metal ofa “supported” graft), and/or concentrated at the ends of the graft (i.e.the proximal and distal vascular anastomoses). They can be utilized tomeasure blood flow through the graft. By comparing the readings ofsensors from one part of the graft to another part of the graft, adetermination of partial narrowing (and the extent of narrowing) can bedetermined (e.g., there would be an decreased blood flow prior to anarrowing or stenosis, and increased blood flow following a narrowing).If the vascular graft was completely obstructed, there would be no flowthrough the graft (before or after the obstruction). The ability tomonitor flow rates would be valuable in normal operation andduring/after procedural attempts to “reopen” obstructed catheters.

Within other embodiments, ISMs having pressure sensors can beincorporated into a graft [e.g., on the outer (adluminal) walls, theinner (luminal) walls and/or within the body of the graft itself (asdescribed above for flow sensors)]. Such sensors are able to measurepressure in or against the vessel wall. Increased pressures can besuggestive of stenosis, thrombosis or kinking upstream from anobstructing event, whereas decreased pressures would be seen downstreamfrom a narrowing and (little or) no pressure would be seen downstreamfrom an obstruction. Having the ability to measure pressure throughoutthe vascular allows for functional monitoring of the graft (in normaloperation and during/after attempts to “reopen” obstructed grafts), andthe capability of detecting events prior to a complication developing.

Within yet other embodiments ISMs having contact sensors can be placedon and throughout the graft in order to measure contact (integrity ofthe seal) between the bypass graft and the vessel to which it isattached (the anastomosis) in order to identify leaks or anastomoticfailure (during and after surgical placement). Contact sensors on theluminal surface of the graft could also detect the presence of unwantedaccumulated luminal surface materials such as restenosis tissue, fibrinor biofilm and alert the clinician to potential problems.

Within further embodiments ISMs having chemical sensors can also beplaced on and throughout the graft in order to measure a wide variety ofimportant metabolic paramaters, including for example: Blood Oxygencontent; Blood CO₂ content; Blood pH; Blood cholesterol; Blood lipids(HDL, LDL); Blood Glucose; Cardiac enzymes; Hepatic Enzymes; and KidneyFunction (BUN, Creatinine, etc.).

Within other embodiments ISMs can be provided with sufficient number ofposition sensors (e.g., on both the luminal and adluminal surfaces, andwithin the graft material itself) in order to allow imaging of thegraft, and detection of changes (such as bending or kinking) and/ormovement over time.

In a particularly preferred embodiment, an ISM containing multiplesensors (flow sensor, position sensor, accelerometer, pressure sensor,contact sensors, chemical sensors, temperature sensors) is located atboth anastomoses of a bypass graft, such that it has luminal surfaceexposure.

Taken collectively, ISMs within vascular grafts can be utilized todetect, measure and assess a number of factors relevant to cardiacfunction. For example, blood flow rate detectors, blood pressuredetectors, and blood volume detectors (e.g., to measure blood volumeover a unit of time) can be placed within (on the luminal side), and onother parts of the vascular graft in order to measure systolic anddiastolic pressure, cardiac output, ejection fraction, cardiac index andsystemic vascular resistance.

Within other embodiments of the invention, vascular grafts (syntheticgrafts and native grafts such as arterio-venous fistulas) can beutilized in a hemodialysis procedure. Briefly, a hemodialysis accessgraft is a vascular graft that is implanted by a vascular surgeon as anartificial, high-flow, interposition graft (or direct anastomosis)between an artery and a vein (typically in the forearm or the thigh) toprovide permanent access for hemodialysis (native arteries and veinstend to collapse and close after being repeatedly instrumented numeroustimes). Once mature and suitable for use, the hemodialysis access graft(or AV fistula) is used as a permanent site into which to insert anothercatheter that is used for exchanging blood to and from a hemodialysismachine. Typically, that catheter has two lumens, one for venous flowand the other for arterial flow (as described in a previous sectionabove). Common complications of hemodialysis access grafts includeclotting, stenosis (narrowing of the graft most often occurring at thegraft-venous anastomosis, but also occasionally at the arterial-graftanastomosis), infection and kinking. Hence, hemodialysis access graftsof the present invention can be utilized which have one or more ISMshaving one or more sensors described herein. For example, within oneembodiment, hemodialysis access grafts of the present invention can havean ISM with one or more blood flow sensors. Such ISMs with blood flowsensors can, within various embodiments be located on the inner(luminal) surfaces of the access graft, within the walls of the accessgraft (e.g., woven into the fabric of a synthetic graft, or incorporatedinto the metal of a “supported” graft), and/or concentrated at thevarious locations (e.g., the ends—the anastomoses—of the access graft).The ISMs with blood flow sensors can be utilized to measure blood flowthrough the hemodialysis access graft. By comparing the readings of ISMflow sensors at various locations in the grafts (for example thearterial and venous anastomses), a determination of partial narrowing(and the extent of narrowing) can be determined (e.g., there would be adecreased blood flow prior to a narrowing or stenosis, and increasedblood flow following a narrowing). If the access graft was completelyobstructed, there would be no flow through the graft (before or afterthe obstruction). The ability to monitor flow rates would be valuable innormal operation and during/after procedural attempts to “reopen”obstructed dialysis catheters (a common interventional procedure).

Within other embodiments, ISMs which have pressure sensors can beincorporated into a dialysis access graft [e.g., on the outer(adluminal) walls, on the inner (luminal) walls, or within the body ofthe access graft itself as described above]. Such sensors are able tomeasure pressure in or against the access graft wall. Increasedpressures within the graft can be suggestive of stenosis (typically atthe graft-vein anastomsis, but occasionally at the artery-graftanastomosis), thrombosis or kinking upstream from an obstructing event,whereas decreased pressures would be seen downstream from a narrowingand (little or) no pressure would be seen downstream from anobstruction. Having the ability to measure pressure throughout thevascular allows for functional monitoring of the graft (in normaloperation and during/after attempts to “reopen” obstructed grafts), aswell as the capability of detecting events prior to a clinicalcomplication developing.

Within yet other embodiments, ISMs having contact sensors can be placedon at the ends of the hemodialysis access graft in order to measurecontact (integrity of the seal) between the access graft and the vesselto which it is attached (i.e. the arterial and venous anastomosis) inorder to identify leaks or anastomotic failure (during and aftersurgical placement). Contact sensors in ISMs on the luminal surface ofthe graft could also detect the presence of surface materials such asrestenosis tissue, fibrin (clot) or biofilm and alert the clinician topotential problems. In yet another example, ISMs having chemical sensorscan also be placed on and/or within the access graft such that thesensors have luminal exposure in order to measure a wide variety ofmetabolic paramaters, including for example: Blood Oxygen content; BloodCO₂ content; Blood pH; Blood cholesterol; Blood lipids (HDL, LDL); BloodGlucose; Cardiac enzymes; Hepatic Enzymes; and Kidney Function (BUN,Creatinine, etc.); parameters which are very important in the clinicalmanagement of a patient with late-stage renal disease.

Within other embodiments ISMs having position sensors can be placedthroughout the hemodialysis access graft (e.g., on both the luminal andadluminal surfaces, and within the access graft material itself) inorder to allow imaging of the access graft, and detection of changes(bending, kinking) and/or movement over time.

Taken collectively, one or more ISMs having wide variety of sensors asdescribed herein can also be utilized to detect, measure and assess anumber of factors relevant to cardiac function. For example, blood flowrate detectors, blood pressure detectors, and blood volume detectors(e.g., to measure blood volume over a unit of time) can be placed within(on the luminal side), and on other parts of the access graft in orderto measure systolic and diastolic pressure, and estimate systemicvascular resistance. Within particularly preferred embodiments ISMshaving one or more blood flow rate detectors, blood pressure detectors,and blood volume detectors can also be utilized to calculate cardiacoutput, ejection fraction and cardiac index (which are key clinicalmeasurements that are valuable in monitoring cardiac-compromisedpatients, which many renal patients are). For example, an ISM containinghigh-fidelity pressure transducers can be located on, in, or within ahemodialysis access graft in order to measure the timing and pressure ofpulsations. Such measurements can be utilized to assess stroke volumeand systemic vascular resistance, and also provide continuous cardiacoutput monitoring and heart rate monitoring. Within yet otherembodiments chemical and temperature sensors can be utilized to monitorchanges in temperature, and/or the presence of an infection or adeveloping infection. With repeated instrumentation of the access graft,the incidence of infection is quite high and monitoring for its presenceprior to the onset of clinical symptoms is of great value to themanagement of the patient.

In a particularly preferred embodiment, an ISM containing multiplesensors (flow sensor, position sensor, accelerometer, pressure sensor,contact sensors, chemical sensors, temperature sensors) is located atone or both ends of the hemodialysis access catheter (i.e. at thearterial and venous anastomoses) such that it has luminal surfaceexposure.

In summary, ISMs with a wide variety of sensors may be placed on and/orwithin hemodialysis access grafts described herein, in order to provide“real time” information and feedback to a health care provider (or asurgeon during a surgical procedure to implant a hemodialysis accessgraft, or an interventionalist performing a procedure to open up anobstructed hemodialysis access graft), to detect proper placement,vascular anatomy, alignment, cardiac output, renal function, infection,and to detect any changes encountered before, during or after aninterventional procedure. For example, the hemodialysis access graftsprovided herein can have one or more ISMs with one or more contactsensors, strain gauge sensors, pressure sensors, fluid pressure sensors,position sensors, accelerometers, shock sensors, rotation sensors,vibration sensors, tilt sensors, pressure sensors, tissue chemistrysensors, tissue metabolic sensors, mechanical stress sensors andtemperature sensors. The above sensors may be continuously monitored inorder to provide a ‘real-world’ activity, healing, and changes infunction over time, to evaluate patient activity, and to betterunderstand the conditions which hemodialysis access grafts are exposedto in the real world.

B.5.A.7. Other Medical Tubes and their Use

Within other embodiments a wide variety of medical tubes are providedwhich may have ISMs with one or more sensors. Representative examples ofmedical tubes include tympanostomy tubes, endotracheal tubes,tracheostomy tubes, nasogastric tubes, gastric tubes, feeding tubes,colostomy tubes, rectal tubes, and chest tubes.

For example within one embodiment one or more ISMS having one or moresensors can be placed on an endotracheal tube. Briefly, an endotrachealtube is a type of catheter that is inserted into the trachea for theprimary purpose of establishing and maintaining a patent airway. Thetube may be orotracheal (inserted into the mouth, nasotracheal (insertedinto the nose), or via a tracheostomy (e.g., inserted via a hole orincision in the trachea).

Within other embodiments the tube having one or more ISMs having one ormore sensors can be a drainage tube such as a chest tube. Briefly, chesttubes (also referred to as ‘chest drains’, thoracic catheters, tubethoracostomy and intercostal drains) are flexible tubes that can beinserted through the chest wall and into the pleural space ormediastinum. Such tubes can be utilized to remove air (e.g.,pneumothorax), fluid (e.g., pleural effusion, blood, chyle), andinfectious material (e.g., empyema, pus)

Chest tubes come in a range of sizes (e.g., 6 Fr to 40 Fr), can havemultiple drainage fenestrations, and optionally, be marked for distance(or length) of the tube, as well as contain radiopaque markers. They areavailable in a wide variety of configurations (e.g., right angle,trocar, flared, and tapered), and may be coated in an effort to preventthrombus formation or clogging. Such tubes can be made from a widevariety of materials, including polyvinyl chloride (“PVC”), silicone,latex, and polyurethane.

Tubes (e.g., tympanostomy tubes, endotracheal tubes, tracheostomy tubes,nasogastric tubes, gastric tubes, feeding tubes, colostomy tubes, rectaltubes, and chest tubes) can suffer from a variety of complications, suchas improper placement, damage to (or penetration into) surroundingtissues, narrowing, obstruction, movement/migration and infection, Forexample, endotracheal tubes have been found to cause a number problems,including aspiration, improper placement, airway obstruction,perforation of the esophagus or trachea, development of a sore throat,pneumonia, narrowing, as well as arrhythmia, hypertension, increasedintracranial pressure, increased intraocular pressure, bronchospasms,laryngospasms, vocal cord damage, retropharyngeal abcesses, nerveinjury, and fistulas.

Hence, tubes of the present invention can be utilized which have one ormore ISMs having a flow sensor as described herein. For example, withinone embodiment chest tubes and endotracheal tubes of the presentinvention are provided with ISMs which have one or more flow sensors.Such sensors can, within various embodiments be located on the inner(luminal) surfaces of the tube, the outer (adluminal) surface of thetube, within the tube, and/or concentrated at the ends of the tube. Theycan be utilized to measure fluid flow through the tube, such as air flow(endotracheal tubes, chest tubes in pneumothorax; note other tubes asdescribed above may have other body fluids passing through them). Bycomparing the readings of sensors throughout the tube, a determinationof partial narrowing (and the extent of narrowing) can be determined(e.g., there would be decreased air flow prior to a narrowing orstenosis, and increased air flow following a narrowing). If the tube wascompletely obstructed, there would be no flow through the tube lumen(before or after the obstruction). The ability to monitor flow rateswould be valuable in normal operation and during/after proceduralattempts to “reopen” obstructed tubes.

Within other embodiments, ISMs containing pressure sensors can beincorporated into a tube [e.g., on the outer (adluminal) walls, theinner (luminal) walls and/or within the body of the tube itself]. Suchsensors are able to measure pressure in or against the tube wall.Increased pressures (e.g. ventilation pressures in endotracheal tubes)can be suggestive of stenosis (narrowing), obstruction or kinkingupstream from an obstructing event, whereas decreased pressures would beseen downstream from a narrowing and (little or) no pressure would beseen downstream from an obstruction. Monitoring pressure in theinflation cuff of an endotracheal tube can ensure that proper inflationis present; not too much pressure so as to lead to mucosal damage to thesurrounding trachea, but not too little so as to allow fluids to pass bythe cuff and aspiration to occur. Having the ability to measure pressureat different locations within the tube allows for functional monitoringof the tube (in normal operation and during/after attempts to “reopen”obstructed tubes), as well as the capability of detecting events priorto a clinical complication developing.

Within yet other embodiments, ISMs containing contact sensors are placedon or within the tube in order to measure contact (integrity of theseal) between the tube and the tissue in which it is placed in order toidentify leaks, cracks, or migration of the tube (during and aftersurgical placement). ISM contact sensors with access to the luminalsurface of the tube could detect the presence of fibrous/inflammatorytissue or biofilm formation and alert the clinician to potentialproblems. Monitoring contact on the surface of the inflation cuff of anendotracheal tube can ensure that proper inflation is present; creatinga sufficient seal between the cuff and the tracheal mucosa such thatfluids are unable to pass by the cuff and allow aspiration to occur.

Within other embodiments, ISMs having chemical sensors are located on orwithin medical tubes for the purpose of measuring a wide variety ofphysiological parameters, including for example: 1) tissue chemistry(e.g., measurement of nitrate, sodium, potassium, calcium andphosphate); 2) the presence of cells (e.g., white cells which maysuggest an infection, and/or red cells which may indicate trauma,erosions/ulcers, penetration of the device into a blood vessel); 3)protein, serous fluid); 4) glucose ketones, bilirubin, urobilinogen,hemoglobin, osmolality, pH, presence of bacteria, tumor markers.

Within other embodiments ISMs containing position sensors are located onor within a medical tube (e.g., on both the luminal and adluminalsurfaces, and within the tube material itself) in order to allow imagingof the tube, and detection of changes and/or movement of the tube overtime. For example, improper placement of endotracheal tubes (usuallyinadvertent placement in the esophagus) is a very dangerouscomplication; 50% of misplacements in the Emergency Room result indeath. Position sensors able to better define the anatomical positionand placement of the medical tube (in “real time”) would be of greatutility. Many other tubes (e.g. proper chest tube placement in the areaof pleura requiring decompression/drainage and not in adjacenttissues—lung, heart, pericardium) would similarly benefit.Post-insertion, many tubes can move from their initial site of placement(e.g., tympanostomy tubes often fall out, endotracheal tubes can migrateinto one of the bronchi to produce uneven ventilation, chest tubes canmove from the required drainage area) and would benefit from the abilityto monitor their movement and current location.

Within yet other embodiments ISMs are provided with chemical and/ortemperature sensors which can be utilized to monitor changes intemperature, and/or the presence of an infection or a developinginfection.

Taken collectively, a wide variety of tubes are provided with ISMshaving one or more sensors as described herein, which can be utilized todetect, measure and assess a number of factors relevant to the functionnumerous implanted tubes. In a particularly preferred embodiment, an ISMcontaining multiple sensors (flow sensor, position sensor,accelerometer, pressure sensor, contact sensors, chemical sensors,temperature sensors) is located at the distal end of the medical tube(i.e. at the tissue contacting end) such that it has luminal surfaceexposure.

In summary, one or more ISMs containing a wide variety of sensors may beplaced on and/or within the medical tubes described herein, in order toprovide “real time” information and feedback to a health care provider(or a physician during an insertion or follow-up procedure), to detectproper placement, anatomy, alignment, forces exerted on surroundingtissues (and entry into, damage to, non-target tissues), integrity,flow, surface conditions, patency and movement/migration of theimplanted tube and to detect and monitor the properties of the fluidsflowing through them. For example, the tubes (e.g., tympanostomy tubes,endotracheal tubes, tracheostomy tubes, nasogastric tubes, gastrictubes, feeding tubes, colostomy tubes, rectal tubes, and chest tubes)provided herein can have one or more ISMs with one or more contactsensors, strain gauge sensors, pressure sensors, fluid pressure sensors,position sensors, accelerometers, shock sensors, rotation sensors,vibration sensors, tilt sensors, pressure sensors, chemistry sensors,metabolic sensors, mechanical stress sensors and temperature sensors.

The above sensors may be continuously or intermittently monitored inorder to provide a ‘real-world’ function, healing, and changes infunction over time, to evaluate patient responses, and to betterunderstand the conditions which tubes are exposed to in the real world.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of sensorsplaced on a medical tube are provided in U.S. Provisional No.62/017,086, which is hereby incorporated by reference in its entirety).

B.6. Implants

Within one embodiment of the invention implants are provided having oneor more ISMs as described herein. Briefly, “implant” as that term isutilized herein, refers to an artificial or synthetic prosthesis thathas, or can be, implanted into a body. Implants are typically utilizedto augment or replace a structure within the body, and have beenutilized in a wide variety of aesthetic applications, including forexample, for facial (e.g., lips, chin, nasal, nasal/labial fold andmalar implants), penile, and body contouring (e.g., breast, pectoral,calf, buttocks, abdomen and biceps/triceps) implants.

“Surrounding Implant” as that term is utilized herein, refers to anartificial or synthetic implant or implanted material that is placedinto the implant pocket where the aesthetic implant will ultimately beinserted. When an aesthetic implant is inserted into the body, a“pocket,” or surgically created anatomical space, is first dissectedinto the tissue which will receive the aesthetic implant. A “surroundingimplant” is typically a gel, adhesion barrier, hemostat, glue, and/oradhesive that is placed into the implant pocket such that it liesbetween the aesthetic implant and the host tissue (bags or other devicescan placed around the aesthetic implant for the same purpose).Generally, the role of the “surrounding implant” is to prevent orminimize (at least initially) the contact between the aesthetic implantand the host tissue in an attempt to reduce scarring and capsularcontraction.

Implants can be composed of a wide variety of materials, but utilizingbreast implants as an example, they are typically comprised of anelastomeric outer surface or ‘shell’, and an interior ‘filling’. Withrespect to the shell, silicone is the most commonly used elastomer,which may be either smooth, or textured. With respect to the filling,most implants are filled with either silicone, or saline (although othercompositions have been suggested, including for example, peanut oil,sunflower oil, soy oil and polypropylene string).

Within various embodiments, the implants may contain more than oneinternal filling (e.g., in different compartments), and may be coated(polymers, gels, drugs) and/or textured on the outer shell or providedwith a bag in order to reduce the incidence of capsular contractions. Inaddition, implants can be provided in different sizes, and differentshapes, and even customized to specific anatomical requirements. Withinyet other embodiments one implant can be delivered to one location inthe breast (e.g., subfascially), and another implant delivered to adifferent location (e.g., subglandularly).

Representative examples of implants are described in U.S. Pat. Nos.4,995882, 6,251,137, 6,464,726, 8,420,077 and U.S. Publication Nos.2006/0136056, 2009/0099656, 2011/0184277, 2014/0088700. Representativeexamples of implant delivery devices include U.S. Pat. No. 8,550,090 andU.S. Publication Nos. 2014/0074235, and 2014/0074236.

The implants and medical devices provided herein are preferably sterile,non-pyrogenic, and/or suitable for use and/or implantation into humans.However, within certain embodiments of the invention the medical devicesand/or kits may be made in a non-sterilized environment (or evencustomized or “printed” for an individual subject), and sterilized at alater point in time.

Within one embodiment of the invention, implants are provided with anISM having one or more sensors as shown in FIG. 19. For example, the ISMhaving one or more position sensors and/or accelerometers can be placedwithin the ‘filling’ of the implant, or on or within the ‘shell’ of animplant. Such sensors are capable of providing: a) an image of theimplant (or ‘real-time’ imaging of the implant); b) assistance duringplacement of the implant, and confirmation subsequent to implant of thecorrect anatomical location (e.g., by way of the aforementioned imaging,or by comparison with external markers); and c) confirmation of fullinflation (i.e. not folded or wrinkled in situ). In addition, suchsensors are useful in confirming that the implant is operating asexpected [e.g., a) confirming that it has not moved or migrated; b)confirming that scarring or capsular contraction has not begun; c)confirming that the integrity of the implant is sound (i.e., that thereare no leaks), or by determination of a leak from the surface of theimplant; and d) confirming that the implant is not wrinkled or folded].Sensors can also be utilized to ensure that acute complications are notdeveloping (e.g., the development of a hematoma, seroma, granuloma,abscess, or other mass in the tissues surrounding the implant thatapplies external pressure to the implant itself).

Within other embodiments, implants are provided with one or more ISMspossessing contact sensors and/or pressure sensors. As noted above, thecontact and/or pressure sensors can be placed within the ‘filling’ ofthe implant, or, on or within the ‘shell’ of the implant. Such sensorsare capable of providing: a) an image of the implant (or ‘real-time’imaging of the implant); b) assistance during placement of the implant,and confirmation subsequent to implant of the correct anatomicallocation (e.g., by way of the aforementioned imaging, or by comparisonwith external markers); and c) confirmation of full inflation (i.e. notfolded or wrinkled in situ). In addition, such sensors are useful inconfirming that the implant is operating as expected [e.g., a)confirming that it has not moved or migrated; b) confirming thatscarring or capsular contraction has not begun; and c) confirming thatthe integrity of the implant is sound (i.e., that there are no leaks),or by determination of a leak from the surface of the implant; and d)confirming that the implant is not wrinkled or folded]. Sensors can alsobe utilized to ensure that acute complications are not developing (e.g.,the development of a hematoma, seroma, granuloma, abscess, or other massin the tissues surrounding the implant that applies external pressure tothe implant itself).

Within yet other embodiments implants are provided with one or more ISMspossessing one or more accelerometers. Such accelerometers can beutilized to a) determine the durability of the implant based upon‘real-world’ conditions; b) determine if different implants are betterin certain patients (based upon activity levels, impact, forces, weight,etc.); and c) assist manufacturers in the design of new implants,product improvements, and collection of clinical data. Moreover, itwould allow the evaluation of performance of different devices undersimilar conditions, and the ability of the patient to monitor theirprogress at home.

Within other embodiments implants are provided with one or more ISMspossessing one or more temperature sensors and/or chemical or metabolicsensors. Such sensors can be utilized to detect the presence ofinfection, seroma, hematoma and inflammation and allow for rapid orpreemptive intervention (e.g., administration of antibiotics before afull-blown infection has developed, drainage of a subclinical hematomaor seroma, or undertake measures to reduce inflammation in an effort tolower the chance of a capsular contracture developing).

It should be obvious to one of skill in the art that ISMs containing thesame sensors can be incorporated into a surrounding implant for the samepurposes as described above.

As will be evident given the disclosure provided herein, a wide varietyof other sensors may also be utilized within the ISM, including forexample, pulse pressure sensors, heart rate sensors, glucose sensors, orsensors to detect tumor (particularly breast cancer) markers.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can contain a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of sensorsplaced on an implant are provided in U.S. Provisional No. 62/017,099,which is hereby incorporated by reference in its entirety).

B.7. Spinal Implants

Within one embodiment of the invention, spinal implants are providedhaving one or more ISMs as described herein. Briefly, “spinal device andor spinal implant” as those terms are utilized herein, refers to a widevariety of devices (typically hardware) and implants (typicallybiomaterials like bone cement and bone grafts) that can be implantedinto, around, or in place of part of a subject's spine (typically in aninterventional or surgical procedure), and which can be utilized tofacilitate vertebral body fracture repair, fusion of vertebrae, correctdegenerative disc disease (DDD), to stabilize the spinal column, and tocorrect deformities due to disease and/or injury. Spinaldevices/implants are typically permanent, but in some cases may betemporary. Representative examples of spinal devices and implantsinclude, for example: spinal cages (e.g., U.S. Pat. Nos. 5,425,772,6,247,847, 6,428,575, 6,746,484, 7,722,674, 7,744,599, 7,988,713,8,172,905, and U.S. Patent App. Nos. 2004/0082953, 2011/0015742,2012/0046750, 2013/0053894, and 2013/0158669): pedicle screws andassociated devices (e.g., U.S. Pat. Nos. 7,678,137, 8,361,121 and U.S.Patent App. Nos. 2005/0187548, 2006/0195086, 2008/0154309 and2009/0287255); artificial discs and associated assemblies (e.g., U.S.Pat. Nos. 5,676,701, 8,226,723, and U.S. Patent App. Nos. 2006/0293753,2007/0088439, 2007/0179611, 2008/0133014, 2011/0054617, and2012/0232662); spinal rods and associated assemblies (e.g. U.S. PatentApp. Nos. 2003/0050640, 2004/0015166, 2007/0118122, 2008/0306528,2009/0177232, 2011/0245875, 2013/0211455, and 2013/0231703), spinalplates and their assemblies (e.g., U.S. Pat. Nos. 8,246,664, 8,262,594,8,343,223, and U.S. Patent App. Nos. 2009/0210008, 2010/0069968, and2013/0006367); and vertebroplasty/kyphoplasty balloons and bone cement(see e.g., US 2007/0100449, US 2009/0299373); all of which areincorporated by reference in their entirety.

Spinal device/implants may be composed of a wide variety of materials(including for example metals such as titanium, titanium alloys, and/orstainless steel), although other materials can also be utilized,including polymers (e.g., polymethylmethacrylate or “PMMA”,poly-ether-ether-ketone or “PEEK” for cervical cages and anteriorthoracolumbar implants, and bone graft material that can be allographic,xenographic or synthetic); growth factors (e.g., bone morphogenicprotein); and non-polymeric materials such as silicon nitride.

“Spinal Implant Surgical Device” or “Spinal Implant Delivery Device”refers to devices that can be utilized to introduce a spinal implantinto a patient, and/or to surgical tools and devices that can beutilized to operate on the spine. Representative examples includeguidewires, trocars, bone tunnel catheters, electrothermal catheters,endoscopes, microsurgical instruments, surgical instruments, kyphoplastyballoons, and bone cement injection devices to name a few.

The medical devices, implants and kits provided herein are preferablysterile, non-pyrogenic, and/or suitable for use and/or implantation intohumans. However, within certain embodiments of the invention the medicaldevices and/or kits may be made in a non-sterilized environment (or evencustomized or “printed” for an individual subject), and sterilized at alater point in time.

B.7.A. Vertebroplasty and Kyphoplasty Procedures

Within various aspects of the invention spinal device/implants andassociated medical devices are provided with ISMs suitable for use in awide variety of vertebroplasty and kyphoplasty procedures. Briefly,vertebral compression fractures can result from the sudden collapse ofthe vertebral body, and result in the rapid onset of back pain,numbness, tingling, weakness, spinal cord compression, and cauda equinesyndrome (e.g., extremity weakness, paraplegia, urinary retention,urinary/fecal incontinence, sexual dysfunction, sciatica, decreasedankle reflex, and saddle anesthesia). It is typically found in patientswith osteoporosis, but can occur due to other causes (e.g., trauma,lytic lesions from metastatic or primary tumors, infections, andosteogenesis imperfecta).

For vertebroplasty procedures, bone cement (e.g., polymethylmethacrylateor “PMMA”) is injected percutaneously into the fractured vertebral bodyin order restore normal vertebral height and anatomy so as to relievethe pain and symptoms associated with compression fractures. Using apercutaneous approach or a small surgical incision, a hole is created inthe wall of the vertebral body by a specialized bone tunneling catheter,followed by introduction of a delivery catheter into the vertebral bodyat the site of the fracture. Bone cement is then injected into thecancellous bone of the collapsed vertebral body until sufficient PMMAmaterial has been injected to restore the vertebra to its normal heightand anatomy (the cement hardens and supports the fractured bone).

Kyphoplasty is a specialized form of vertebroplasty. In kyphoplastyprocedures, a balloon is first inserted into the cancellous bone of thevertebral compression fracture and then inflated in order to restorenormal vertebral height and spinal shape (kyphosis) and to create avoid. The balloon is then removed and PMMA is injected into the voidcreated by the balloon and allowed to harden in place to form a solidsupport structure within the fractured vertebrae. A number of medicalinstruments can be utilized to complete a kyphoplasty, including, anintroducing needle, an injector for the bone cement, bone needles,guidewires, bone tunnel catheters, balloon introducing catheters and akyphoplasty balloon catheter.

Within various embodiments of the invention, ISMs containing sensors maybe placed in some or all of the spinal implants and associated devicesused for vertebroplasty and/or kyphoplasty.

For example, as shown in FIG. 20, a hole is created in the vertebralbody (FIG. 20A) through a bone tunneling catheter; an ISM is introduced(FIG. 20B); followed by a delivery device (FIG. 20C) which allowsinjection of the bone cement directly into the collapsed bone. Thecompression fracture is corrected and supported through the injection ofbone cement into the vertebral body (as shown in FIGS. 20D and 20E) torestore the normal height of the vertebra.

Similarly, as shown in FIG. 21, one or more ISMs can be placed on, orwithin the kyphoplasty balloon. The ISM can have pressure sensors inorder to monitor pressure exerted on the cancellous bone by thekyphoplasty balloon (particularly during inflation) and to optimize theinflation pressure (preventing over-inflation leading to potentialtissue damage) and deflation pressure (ensuring the balloon is fullydeflated before attempting to remove the device). ISMs containingcontact sensors can also be placed on or within the kyphoplasty balloonin order to monitor contact between the balloon and the cancellous boneof the vertebral body. Similarly, ISMs containing positionsensors/location markers can be placed on or within the kyphoplastyballoon in order to assist in accurate placement of the insertiondevice, the balloon, and bone cement into the compression fracture.Position sensors and location markers are also useful to monitor theexpansion of the vertebral body (by, for example monitoring the positionof the balloon walls as the balloon is progressively inflated) toachieve a more precise expansion; one that can be more accuratelymatched to the anatomical deficit present. “Visualization” via the ISMsensors present on the balloon assist with accurate placement, optimumexpansion, more precise measurement of deficit correction and safedeflation and extraction; all completed in “real time” during theprocedure. In a preferred embodiment, one or more ISMs contained on orwithin the kyphoplasty balloon contain several sensors includingposition sensors, location markers, accelerometers, pressure sensors,and contact sensors.

ISMs having sensors may have a variety of additional uses, including toassist in identifying vertebral anatomy (e.g., to measure the exactvertebral height restored and proper kyphosis during kyphoplasty), toprevent accidental placement of the kyphoplasty instruments intosurrounding tissues (the spinal cord, spinal nerves, etc.), to confirmfull (or optimal) balloon inflation and deflation, to confirmrestoration of vertebral height and kyphosis after kyphoplasty, and toimage the void where bone cement will be injected, to more preciselymatch the volume to be injected, and to prevent overfilling and/leakageof the bone cement. Within various embodiments of the invention ISMs, orpassive sensors along with the ISMs can be added to the bone cement, andutilized to interrogate various aspects of the procedure (as notedabove), as well as ultimate success and maintenance of the procedure(See FIGS. 20 and 21). An ISM containing accelerometers can be placedwithin the bone cement in order to detect acceleration, vibration,shock, tilt and rotation of the cement within the vertebral body. Suchsensors may be utilized to create 2D and 3D imaging data which show thesize and shape of the filled void, movement and/or dissolution of thebone cement, and potentially complications such as leakage orimpingement of the cement into the spinal cord and/or around the spinalnerves. Within preferred embodiments the image data can be collectedover time, in order to visually show changes (e.g., a “movie” or ‘movingimages”) detected by the sensors.

In a preferred embodiment, one or more ISMs contained within the bonecement contain several sensors including position sensors, locationmarkers, accelerometers, pressure sensors, and contact sensors in orderto monitor spinal anatomy, function and the development of side effects.

Optionally, ISMs containing chemical sensors and placed within the bonecement can be utilized to monitor pH, calcium content, and otherparameters (e.g., in order to predict and/or monitor the progression ofosteoporosis, tumor growth and/or bone metabolism). Similarly,temperature sensors, can be utilized to monitor the temperature of thecement (the cement is above body temperature when initially insertedbefore hardening), as well as indicate any possible early signs ofinflammation or infection.

The above described ISMs within bone cement can be utilized to monitorpressure, location, position, contact and other measures (temperature,pH, etc.) during both placement and in subsequent follow-up. Onceimplanted, the ISM contained within the bone cement is identical,regardless of whether it is administered as part of vertebroplasty (FIG.20) or kyphoplasty (FIG. 21).

The above ISM containing sensors may be continuously monitored in orderto provide a ‘real-world’ range of motion for the spine, to assist indetecting any decrease in spinal health, to collect and compareprocedure performance data over time, to evaluate patient function, andto better understand the conditions which spinal implants are exposed toin the real world.

B.7.B. Intervertebral Disc Disease/Spinal Fusion

Injury and/or disease of the intervertebral disc can result insubstantive, chronic neck and/or back pain and/or neurological symptoms.Examples of chronic disc problems include degenerated discs, bulgingdiscs, herniated discs, thinning discs, and disc degeneration withosteophyte formation.

In order to address problems associated with intervertebral discinjuries or disease, spinal fusion surgery is often indicated. In thissurgery, two or more adjacent vertebrae (vertebral bodies) are fusedtogether by creating a ‘bony bridge’ across the damaged/diseasedintervertebral disc, for example, by using autologous or allograph bonetissue. For posterolateral spinal fusion a bony fusion is createdbetween the transverse processes of the vertebrae, while in an interbodyspinal fusion the bone graft is created between the bodies of thevertebrae in the area usually occupied by the intervertebral disc. Inthe latter case the disc is often removed entirely and is typicallyreplaced by a plastic or titanium cage to maintain alignment and heightand promote bone growth. Fusion may also be augmented by fixationdevices, including metal screws (including pedicle screws and a rod),rods or plates to connect the screws, and wires.

Spinal fusion devices, and spinal fusion surgery in general can beassociated with many complications, both during the surgery, as well aspost-surgically. Typical complications include vertebral subluxation(abnormal movement between the vertebra), collapse of structuralelements and loss of support, tissue-reaction against the device,infection, pseudo-arthritis, failure to heal properly (i.e., delayedunion or non-union of the vertebrae) and problems with the implanteddevices themselves such as: hardware fracture, loosening and/ormigration; pedicle screw breakage, loosening or movement: andtransitional syndrome (i.e., stress placed on nearby vertebrae due tothe fusion).

Within various embodiments of the invention ISMs having one or moresensors can be placed on the instruments and fixation devices describedherein in order to assist placement of the medical device and/orimplant, and to monitor for efficacy subsequent to surgery. For example,ISMs can be placed on rods which are affixed by pedicle screws (FIG.22A), as well as on plates which can be utilized to fuse to vertebraetogether (FIG. 22B). It should be evident given the disclosure providedherein that the ISMs can also be placed on or within the pedicle screws,wires and/or other hardware used in spinal fusion.

For example, the ISMs shown in FIGS. 22A and 22B can have positionsensors that can be utilized to assess the range of motion of the spinalsegment (flexion and extension of the spinal segment, adduction androtation of the spinal segment), to enhance the accuracy of physicalexam (from 3D data which may be utilized to produce an image, and toassess position and movement of the spine and the device, to assess ifthere is subluxation between the segments), to monitor spinal and deviceanatomy (alignment, kyphosis), to assess the contact and interactionbetween adjacent device components (e.g., between screws, plates rodsand/or wires), and to monitor for breakage, bending, loosening and/ormovement of any of the implant parts. Collection of data from positionsensors will also allow for both short-term and long-term assessment ofproduct performance, as well as assessment of healing and patientrecovery.

The ISMs shown in FIGS. 22A and 22B can also have contact sensors thatcan be utilized to detect the space, movement and integrity of the bondbetween the hardware and the surrounding tissues, and the integrity ofthe connections between the various different pieces of hardware(disconnection of the hardware components), bending or breakage of thehardware pieces, and to detect loosening and/or osteolysis associatedwith the hardware (bone loss in the tissues surrounding the implanteddevices; particularly for screws). Collection of data from contactsensors will also allow for both short-term and long-term assessment ofproduct performance, as well as assessment of healing and patientrecovery.

The ISMs shown in FIGS. 22A and 22B can also have accelerometers and/orstrain gauges that can be utilized to indicate strains (and/orrepetitive strains over time) that can result in destructive boneremodeling. In addition, the sensors can detect and record themagnitude, direction of acceleration, orientation, vibration and shockof a given strain. Hence, loosening of screw in bone, movement betweencomponents, vertebral subluxation (spondylolisthesis), breakage and/orfailure of components, and the collapse of structural elements(including damage to the surrounding bone) can also be monitored andrecorded. The data can also be integrated and utilized to create a 2Dand/or 3D image of the hardware and spinal anatomy, both at a singlepoint as well as over time based upon real-world stresses. Such sensorsalso allows for the continuous monitoring of the device in order toassess both short-term and long-term assessment of product performance,as well as assessment of healing and patient recovery.

A wide variety of other sensors (alone or in combination) can also becontained within the ISMs shown in FIGS. 22A and 22B, including forexample, one or more contact sensors, strain gauge sensors, pressuresensors, fluid pressure sensors, position sensors, accelerometers, shocksensors, rotation sensors, vibration sensors, tilt sensors, pressuresensors, tissue chemistry sensors, tissue metabolic sensors, mechanicalstress sensors and temperature sensors.

B.7.C. Degenerative Disc Disease (DDD)/Interbody Fusion/Spinal Cages

Degenerative Disc Disease, also known as spondylosis, is typically adisease associated with aging (although it can also be caused by injuryor trauma), and can be associated with chronic neck and/or back pain andperipheral nervous symptoms (numbness, tingling, weakness, bowel andbladder problems). Fibrocartilage typically develops in theintervertebral disc as a result of aging or repeated injury. Contents ofthe nucleus pulposis (the inner, gelatinous part of the disc) can bulgeor herniate through weakened areas of the annulus fibrosis and come intocontact with the spinal cord or the spinal nerves. It is the pressurefrom the bulging or herniated disc on the spinal cord or the spinalnerves that leads to the pain and neurological symptoms describedpreviously.

Spinal cages have been developed in order to assist with interbodyfusion, and can be utilized to treat Degenerative Disc Disease,herniated discs, and low grade spondylolisthesis. They are typicallysmall, hollow cylindrical devices composed of titanium, titanium alloys,stainless steel, or polymers. They can be filled with bone graftmaterial (allograft or autograft) and/or growth factors (e.g. bonemorphogenic protein, BMP)

A wide variety of spinal cages are presently available commercially froma number of manufacturers (e.g., BAK from Sulzer Spine Tech, Ray TFCfrom Stryker, Contact Fusion Cage from Synthes, and Interfix Cage and LTCage from Medtronic). Spinal cages can be manufactured to be placedbetween the vertebral bodies of the spine in a specific orientation(e.g., a vertebral body side and a vertical side). Furthermore, thevertical sides can be flattened to allow the placement of two cagesside-by-side in the intervertebral space. The spinal cage can be packedduring surgery with autologous or allogeneic bone graft material, withor without other factors such as bone morphogenic proteins (“BMPs”), inorder to assist in bone growth through the perforated walls of the cage,and the formation of a bony fusion between the vertebrae.

Within various embodiments of the invention, ISMs having sensors can beplaced on and/or within a spinal cage (e.g., as shown in FIG. 23). Forexample, an ISM having position sensors can be placed on and/or within aspinal cage and/or within the bone graft material. The sensors can beutilized to detect and monitor location and fixation of the affectedspinal cage, movement of the cage within the intervertebral space, tomonitor breakage and/or wear of the spinal cage, and to monitor theanatomy, contact and interaction between adjacent components(particularly when more than one cage is used),. For example, duringplacement, the ISM position sensors can be utilized to determine if thecages are correctly placed, if spinal alignment is correct, and ifintervertebral spacing is optimal; following placement, the ISM positionsensors can monitor any movement, migration, or breakage of the spinalcage; furthermore, they can be used to follow the progress of bonyfusion as spinal cage movement should become progressively less as newbone growth successfully fuses the two segments together (and “locks”the cages within the bone mass); conversely, ongoing positional movementor increasing positional movement would be cause for concern that fusionis not progressing as expected. ISM positional sensors therefore allowfor the continuous monitoring of the device, spinal anatomy (alignment,spacing, etc.) and bony fusion in order to assess both short-term andlong-term product performance, as well as assessment of healing andpatient recovery.

Within other embodiments, ISMs containing contact and/or pressuresensors can be placed on or within the spinal cage (as shown in FIG. 23)and/or within the bone graft material. Within certain embodiments of theinvention two cages are provided with ISMs which allow “matching” sensorplacement, in order to allow an analysis of movement and/or migrationbetween the different (paired) pieces of spinal cage hardware. Contactsensors can also be utilized to detect space, movement, and theintegrity of bond between the hardware and the developing bony tissue.For example, increasing contact and/or decreasing pressure between thehardware and the surrounding tissue is suggestive of ongoing fusion(i.e. the new bone growth is assuming the compressive forces anddecreasing the dependence on the cage), while eventual contact/pressurestabilization suggests healing is almost complete; such measurements canguide rehabilitation and physiotherapy decisions. On the other hand,lessening of contact between the bone tissue and the cage might suggestinadequate bone growth, failure of fusion, or failure of the device;increasing pressure on the cage in this context would suggest that thedevice (and not the new bone growth) is taking a disproportionate amountof the compressive forces between the intervertebral bodies. The sensorsalso allow for the continuous monitoring of the device in order toassess both short-term and long-term product performance, as well asassessment of healing and patient recovery and can help guide activityand recovery regiments.

Within yet other embodiments, ISMs containing accelerometers and/orstrain gauges can be placed on or within the spinal cages (as shown inFIG. 23) and/or within the bone graft material. The ISM accelerometerscan be utilized to detect and record the magnitude, direction ofacceleration, orientation, vibration and shock of a given strain. Hence,detection of vibration/movement may indicate loosening within the fuseddisc, movement between paired spinal cage components (if more than onecage is used), breakage/failure of the spinal cage, migration of thecage(s), vertebral subluxation (spondylolisthesis), collapse ofstructural elements and loss of support, as well as damage tosurrounding new bone. Data which is generated from the sensors can alsobe integrated and utilized to create a 2D and/or 3D image of thehardware and spinal anatomy, both at a single time point, as well asover time, based upon real-world stresses. Accelerometers can providethe clinician with an understanding of the overall movement andstability of the affected spinal segment—the flexion, extension androtation of the spinal segment (which if bony fusion is successful,should all decrease with time). Such sensors also allow for thecontinuous monitoring of the implanted device in order to monitor bothshort-term and long-term product performance, as well as assessment ofhealing and patient recovery. This data is helpful in monitoring patientprogress and the effects of specific rehabilitation efforts as well asidentifying potential activities/actions that are detrimental torecovery.

As will be evident given the disclosure provided herein, in addition tothe above noted sensors, the ISM on the spinal cage of FIG. 23 (or inthe bone graft material) may also have a variety of sensors, includingfor example, one or more contact sensors, strain gauge sensors, pressuresensors, fluid pressure sensors, position sensors, accelerometers, shocksensors, rotation sensors, vibration sensors, tilt sensors, pressuresensors, tissue chemistry sensors, tissue metabolic sensors, mechanicalstress sensors and temperature sensors.

B.7.D. Artificial Discs

Within various aspects of the present invention, intervertebral discdamage (e.g., injury or disease such as Degenerative Disc Disease) mayalso be treated utilizing artificial discs (i.e., by completereplacement of the damaged disc with a prosthetic replacement). Theintent of an artificial disc is, unlike a spinal fusion, to preservemotion between the vertebrae, e.g., to provide for more natural spinalflexion, extension and rotation. Representative artificial discs includethe Charite Lumbar Disc (DePuy), Prodisc Lumbar Disc (Synthes), ProDiscCervical Disc (Synthes) and the Maverick Lumbar Dis (Medtronic).Typically, the intervertebral disc is completely excised by the surgeonvia an anterior (abdominal) approach, and plates (usually composed oftitanium or titanium alloys) are placed over the vertebral bodies. Acore piece (usually comprised of a polymer such as polyethylene) issized to provide the correct height and positioned between the plates inorder to complete the artificial disc.

Within an embodiment of the invention, artificial discs are providedwith one or more ISMs (see, e.g., FIG. 24). For example, within oneembodiment, artificial discs are provided with an ISM having one or morepositions sensors placed on and/or within the artificial disc (i.e., onor within the metallic plates, and/or on/within the articular core piecebetween the plates). For artificial discs that a cemented in place, theone or more ISMs can also be contained within the bone cement.Intraoperatively, the ISM position sensors can be utilized by thesurgeon to determine accurate placement, alignment and spinal anatomy(medical imaging). Postoperatively, the ISM Position sensors can beutilized to detect and accurately monitor flexion, extension androtation of the artificial disc (precise, numeric measurements of allmotion), and to assess, measure and evaluate the range of motion of thespinal segment. The ISM position sensors can also be utilized todetermine and monitor the location and fixation of the artificial disc,movement of the artificial disc, to monitor the anatomy, contact andinteraction between adjacent components (detect normal componentmovement and abnormal component movement such as artificial jointdislocation or subluxation), and to monitor migration, breakage and/orwear of the artificial disc. It also allows for the continuousmonitoring of the device in order to assess both short-term andlong-term product performance, as well as assessment of healing andpatient recovery.

Within other embodiments, the ISM of FIG. 23 can have one or morecontact sensors, and be placed on and/or within the artificial disc(i.e., on or within the metallic plates, and/or on/within the articularcore piece between the plates); for cemented prostheses, the ISM can becontained within the bone cement. Intraoperatively, the ISM contactsensors can be utilized by the surgeon to determine accurate placement,alignment and contact between the metallic plates and the surroundingtissues and between the components of the artificial disc (the metallicplates and the articular core). Postoperatively, the ISM contact sensorscan also be utilized to detect space, movement, and the integrity ofbond between the disc hardware (the metallic plates) and bone, and todetect increasing movement (which could be suggestive of osteolysis); tomonitor articular surface contact (to identify artificial jointdislocation or subluxation); and to detect and/or monitor wear, erosion,migration and/or failure or breakage of the device. An ISMs can also beplaced at critical depth within the polymeric articular core to notifythe patient and physician when the amount of surface wear of thesynthetic articular component has become concerning. The sensors alsoallow for the continuous monitoring of the device in order to assessboth short-term and long-term product performance, as well as assessmentof healing and patient recovery.

Within other embodiments, the ISMs of FIG. 23 can have one or moreaccelerometers and/or strain gauges and can be located on and/or withinthe artificial disc (e.g., on or within the metallic plates, and/oron/within the articular core piece between the plates); for cementedprostheses, the ISM can be contained within the bone cement). The ISMaccelerometers can be utilized to detect and record the magnitude,direction of acceleration, orientation, vibration and shock of a givenstrain. Hence, detection of vibration/movement may indicate loosening ofthe prosthetic disc from the surrounding bone (improper fixation orosteolysis); or within the artificial disc, vibration/movement may be anindicator of migration/breakage/failure of the artificial disc,vertebral artificial joint subluxation or dislocation, collapse of thestructural elements and loss of support, as well as damage tosurrounding new bone. Data which is generated from the ISMaccelerometers can also be integrated and utilized to create a 2D and/or3D image of the hardware and spinal anatomy, both at a single point aswell as over time based upon real-world stresses. ISM accelerometers canprovide the clinician with an understanding of the overall movement andstability of the affected spinal segment—the flexion, extension androtation of the spinal segment containing the artificial disc. Suchsensors also allow for the continuous monitoring of the device under“real world” conditions in order to assess both short-term and long-termperformance, as well as assessment of healing and patient recovery. Thisdata is helpful in monitoring patient progress and the effects ofspecific rehabilitation efforts as well as identifying potentialactivities/actions that are detrimental to recovery.

In summary, a wide variety of ISMs having sensors may be placed onand/or within the artificial disc (i.e., on or within the metallicplates, and/or on/within the articular core piece between the plates;for cemented prostheses, the ISMs can also be contained within the bonecement) in order to provide an evaluation of performance in the clinicas well as in ‘real-world’ settings, to detect loosening between theprosthesis and the surrounding bone, to detect joint subluxation ordislocation, to monitor spinal anatomy and alignment, to detectinfection and/or inflammation, to detect the strain encountered in theprosthesis, to detect acceleration and impact events, and to detectarticular surface wear in the metal plates and/or polymer components (ifpresent). For example, the ISM contained on or within an artificial disccan have a combination of one or more contact sensors, strain gaugesensors, pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors.

B.7.E. Microdiscetomy

Within various aspects of the present invention, devices and methods areprovided for treating herniated discs. Briefly, unlike a typicalvertebrae, a tear in the Annulus Fibrosis of the disc allows the soft,central Nucleus Pulposis to herniate out through the Annulus. This mayoccur for a variety of reasons, e.g., trauma, lifting, repeated injury,or may be idiopathic in nature. Such herniated discs may be initiallytreated conservatively with rest, anti-inflammatory medication, andphysiotherapy, but in certain cases, surgery may be required if thenerve roots or spinal cord are involved and neurological symptoms(numbness, weakness, tingling, paralysis, bowel or bladder dysfunction)are present.

In a typical surgical procedure, a patient is anesthetized, and a smallincision is made in the back. The spinal muscles and ligaments areseparated, and a small amount of the facet joint may be removed. Theherniated disc material is then removed endoscopically.

Within various embodiments, microdiscectomy tools containing ISMs withsensors, as described herein, are provided. For example, within oneembodiment microdiscectomy tools containing ISMs with contact sensorsare provided which can be utilized to monitor contact between therongeur and nerve root, spinal cord and/or surrounding nerve tissue.Microdiscectomy tools containing ISMs with pressure sensors may beutilized to monitor pressure exerted on the nerve tissue duringdissection, and to prevent tissue damage and nerve injury from excessivepressure. Microdiscectomy tools containing ISMs with position sensorsand accelerometers can be utilized to assist in resection of herniateddisc tissue, and used for medical imaging (e.g., to provide an image ofspinal and disc anatomy, the herniated segment, and disc wall) pre andpost-resection. Within certain embodiments of the invention, a naturallyoccurring or synthetic nucleus-like material may be reinjected back intothe disc (see generally, Eur Spine J. 2009 November; 18(11): 1706-1712.Published online 2009 Aug. 18). Within preferred embodiments, thenaturally occurring or synthetic nucleus-like material may contain oneor more ISMs having sensors to monitor pressure, position, contactand/or movement within the nucleus, as well as leaks or ruptures of thedisc and inflammation and/or infection of the disc.

Within other aspects of the invention, Intradiscal ElectrothermalAnnuloplasty can be utilized to treat, for example, Degenerative DiscDisease. For example, an electrothermal catheter can be inserted alongthe back inner wall of the disc. The catheter can then be heated,thereby thickening collagen fibers which make up the disc wall (andsealing any ruptures in the disc wall), and cauterizing sensitive nerveendings.

Within various embodiments of the invention electrothermal catheters areprovided comprising one or more ISMs having sensors that can be utilizedin the process of Intradiscal Eletrothermal Annuloplasty. For example,ISMs having contact sensors can be utilized to monitor contact betweenthe electrothermal catheter and the inner wall of the annulus. ISMshaving pressure sensors can be utilized to monitor the pressure in theannulus, to aid in avoiding perforation through the annulus, and toconfirm the integrity/sealing of the annulus post-procedure. ISMs havingposition sensors and accelerometers can be utilized to assist incatheter placement, and used for medical imaging (e.g., to confirmcorrect catheter placement and to image spinal anatomy and disc anatomy,both pre and post-treatment). In addition, ISMs having temperaturesensors can be utilized to control the heat of the catheter, in order toascertain and maintain the correct operating temperature (and preventthermal injury to non-target tissues).

In summary, one or more ISMs having one or more sensors may be placed onand/or within microdiscectomy and electrothermal catheter tools in orderto provide “real time” information and feedback to the surgeon duringthe procedure, to detect instrument placement, spinal and disc anatomy,forces exerted on surrounding tissues, and to detect the physiologicconditions encountered in an interventional procedure. For example, themicrodissectomy and electrothermal tools can have one or more ISMshaving one or more contact sensors, strain gauge sensors, pressuresensors, fluid pressure sensors, position sensors, accelerometers, shocksensors, rotation sensors, vibration sensors, tilt sensors, pressuresensors, tissue chemistry sensors, tissue metabolic sensors, mechanicalstress sensors and temperature sensors.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can contain a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of sensorsplaced on a spinal implant or spinal device, or spinal implant surgicaldelivery device are provided in U.S. Provisional No. 62/017,106, whichis hereby incorporated by reference in its entirety).

B.8. Orthopedic Hardware

Within one embodiment of the invention, ISMs are provided in orthopedichardware and/or orthopedic implants. “Orthopedic device and/ororthopedic implant” as those terms are utilized herein, refers to a widevariety of devices (typically hardware) and implants (typicallybiomaterials like bone cement, glues, adhesives, hemostats and bonegrafts) that can be implanted into, around, or in place of part of asubject's musculoskeletal system (e.g., bone), in order to facilitatetreatment of the disease, injury or disorder. Representative conditionsthat may be treated include musculoskeletal trauma (e.g., falls, trauma,motor vehicle accidents, projectile injuries), sports injuries,degenerative diseases (such as osteoarthritis and other forms ofarthritis, osteoporosis), infections (osteomyelitis), tumors (primaryand metastatic bone tumors), and congenital disorders (deformities,osteogenesis imperfect).

Orthopedic devices and implants can be utilized both externally andinternally to correct musculoskeletal injuries and deformities.Representative examples of external orthopedic devices and implantsinclude, for example: casts (e.g., made of plaster of paris,polyurenthane, fiberglass, or thermoplastics; see, e.g., U.S. Pat. Nos.4,308,862, 4,817,590, 6,053,882), braces (see e.g., U.S. Pat. Nos.4,862,878 and 5,437,617), tensor bandages (e.g., elastic bandages whichare stretchable and can create localized pressure; e.g., Kendall TensorElastic Bandages), slings, supports and braces (e.g., ACE AdjustedPadded Sling, and Flexibrace®), (see generally “Orthopedic Taping,Wrapping, Bracing & Padding”, Joel W. Beam, F. A. David Company, 2006).

Representative examples of internal hardware and implants includeK-wires (Kirschner wires), pins (Steinmann pins), screws, plates, andintramedullary devices (e.g., rods and nails) and associated devices.Briefly, intramedullary rods or nails (including for exampleinterlocking nails, Küntscher nails, Ender's nail, Grosse-Kempf (GK)nails, Gamma nails, and Rush nails) are long metal rods which areimplanted into the medullary cavity of a long bone (e.g., a femur,humerus, or tibia), thereby providing greater stability and support tothe bone during healing. Kirschner wires (or “K-wires”) are sharpened,smooth pins which are utilized to hold bone fragments together, or toserve as an anchor for skeletal traction. K-wires come in a variety ofsizes and shapes, and within certain embodiments may be threaded.Orthopedic screws, pins and plates are utilized in a wide variety oforthopedic procedures to secure, stabilize, mend, fix, replace, orimmobilize bone (or bone fragments). Representative orthopedic implantsinclude Smith Peterson nails for fracture of the neck of the femur,McLaughin's plate (which along with Smith Peterson nails are used forinter-trochanteric factures), Buttress plates for condylar fractures ofthe tibia, the Condylar blade plate for condylar fractures of the femur,Dynamic compression plates, Steinmann pins for skeletal traction,Talwalkar nails for fractures of the radius and ulna, and Moore's pinfor fractures of the head of the femur. Representative examples of theabove devices, implants and devices are described in Oxford Textbook ofOrthopedics and Trauma, Oxford University Press, 2002; (see also U.S.Pat. Nos. 6,565,573, 7,044,951, 7,686,808, 7,811,311, 7,905,924,8,048,134, and 8,361,131) all of the above of which are incorporated byreference in their entirety.

Orthopedic devices or implants may be composed of a wide variety ofmaterials (including for example metals such as titanium, titaniumalloys, and/or stainless steel), although other materials can also beutilized, including polymers (e.g., polymethylmethacrylate or “PMMA”,poly-ether-ether-ketone or “PEEK”, and bone graft material that can beallographic, xenographic or synthetic); and non-polymeric materials suchas silicon nitride.

Within certain embodiments of the invention, ISMs can be placed intoorthopedic devices which are traditionally made of metallic materials(e.g., plates) by a variety of different means. For example, within oneembodiment small holes, cavities, or openings can be placed into adevice (e.g., through use of a laser), and one or more sensor insertedinto the opening. Within other embodiments, a surface of a metallicdevice can be coated with one or more polymers which contain or compriseone or more ISMs having one or more sensors. Within other embodiments,the ISM can be inserted into the “shaft” of the device (intermedullaryrods, pins or nails; dynamic hip screws) or attached to the devicesurface.

“Orthopedic implant surgical device” or “orthopedic implant deliverydevice” refers to devices that can be utilized to introduce anorthopedic implant into a patient, and/or to surgical devices that canbe utilized to operate on the bone. Representative examples includepower drills, power screw devices, and power saw devices, mallets,hammers, and chisels all of which are composed of selected sterilizablecomponents. Other examples include glue, hemostat, and bone cementinjection devices.

The medical devices (e.g., orthopedic devices and implants, orthopedicdelivery devices, etc.) and kits provided herein are preferably sterile,non-pyrogenic, and/or suitable for use and/or implantation into humans.However, within certain embodiments of the invention the medical devicesand/or kits may be made in a non-sterilized environment (or evencustomized or “printed” for an individual subject), and sterilized at alater point in time.

B.8.A. External Orthopedic Devices: Casts, Splints, Braces, Tensors,Slings and Supports

As noted above, within various aspects of the invention, externalorthopedic devices or implants and associated medical devices areprovided for use in a wide variety of orthopedic procedures.

For example, within one embodiment of the invention ISMs can be placedonto, within, and/or under casting material (e.g., typically plaster ofparis on a mesh, fiberglass mesh, or a polymer—based composition such aspolyurethane or a thermoplastic polymer), in order to form a cast.Within other embodiments one or more ISMs can be placed on the surfaceof, within, and/or under the 3-D printed cast.

Such ISMs can be utilized for a variety of purposes. For example, one ofthe complications associated with casts is the development of points ofpressure between the cast and the skin, which can result in tissuesores, pain, and even tissue necrosis. ISMs having pressure sensors canbe utilized to detect pressures during placement of the cast, as well asover the period that the cast is in place. The pressure sensors can beutilized to monitor inappropriate or dangerous increases in pressure(which can occur, for example, with inflammation occurring in the daysfollowing injury or after ambulation), and to serve as a basis to alerta patient, health care provider, or other entity or object as discussedin more detail below.

ISMs having accelerometers and/or position sensors can be utilized incasts in order to monitor joint movement and immobilization, and toensure that too much stress is not placed on the casted body part.Proper fracture healing often requires not only immobilization of thebone fragments, but also the immobilization of the joints above andbelow the fracture. Accelerometers and/or position sensors can help toensure that the underlying structure (e.g., bone) maintains properalignment and that the related joints are adequately immobilized. Inaddition, the ISM accelerometers and position sensors can be utilized tomonitor twisting, torque, flexion, extension and bending, all of whichmay lead to complications such as inadequate or improper healing.

Within certain embodiments, ISMs having external accelerometers and/orposition sensors may be correlated with sensors which have been placedwithin the body (e.g., implanted by injection or surgically, orassociated with an internal orthopedic implant as described in moredetail below).

For example, as shown in FIG. 25, ISMs (e.g. ISMs having one or more ofaccelerometers, position sensors, pressure sensors, etc.) can be placedon an external support structure (e.g. see FIG. 25A). ISMs (e.g. ISMshaving one or more of accelerometers, position sensors, pressuresensors, etc.) can be placed on various aspects of the support structure(including for example on external screws, pins, clamps or othersupporting structures), as well as on various aspects of the orthopedicdevices or implants inserted on or into a bone (e.g., the radius asshown in FIG. 25B implanted on the arm (FIG. 25C). Movement between theinternal (implanted) sensors and external sensors can be utilized toassess whether anatomical segments have become misaligned, and whethersuch misalignment might need to be adjusted or corrected in a furtherprocedure.

Within yet other embodiments ISMs having chemical and temperaturesensors can be utilized to monitor skin temperature, skin integrity,and/or the presence of an infection or a developing infection. ISMsensors positioned on casts and splints in contact with the skin areideally located to serve this function.

Within other embodiments of the invention, ISMs can be placed on avariety of supports, braces, slings, splints, and tensors. For example,as shown in FIG. 26, one or more ISMs can be placed on knee braces (FIG.26A), head and neck braces (FIG. 26B), tensor bandages (not shown), armslings (not shown) and back braces (not shown).

Within other embodiments of the invention, ISMs can be placed at avariety of locations within a sports helmet designed to protect thesporting participant such as but not limited to football, ice hockey,and lacross helmets. ISMs with accelerometers and gyroscopes can measureimpact G-force sustained during play and monitor acute and cumulativeconcussive effects for real time assessment of potential brain injury.

Within various embodiments, ISMs having one or more pressure sensors canbe placed in any of the braces, tensors, slings or supports providedherein. ISMs with pressure sensors can be utilized to measurecompression, rotation and axial loading, and the amount of support.Detection of increased pressure can indicate the possibility of, orpotential for, skin and or tissue damage. Detection of decreasedpressure can indicate that the device might be ineffective and/or needreapplication or replacement. A rapid increase or decrease in pressurecan indicate a traumatic event. For example, detection of a rapidincrease in pressure could indicate swelling, inappropriate motion,and/or a risk of breakage or injury, or even the development of acompartment syndrome. A rapid decrease in pressure could indicate atotal failure of the device.

Within other embodiments of the invention, ISMs having accelerometers(and strain gauges) can be placed in any of the braces, tensors, slings,splints or supports provided herein. ISMs containing accelerometers canbe utilized to monitor alignment, stability and healing. They can alsobe utilized to monitor and assess patient activity levels (e.g., dailyfunction, range of motion, physiotherapy, rehab and exercise), and tomonitor for rotation, bending, breakage, movement and/or slippage of thedevice.

Within other embodiments of the invention, ISMs having position sensors(and locations markers such as GPS) can be placed in any of the braces,tensors, slings, splints or supports provided herein. ISMs containingposition sensors (and location markers) can be utilized to monitor forexample, any changes in anatomy, alignment, or mobility. In addition,through the use of location sensors, patient activity, compliance,mobility/immobility, the effect of rehab, and falls, breakage oremergencies can all be monitored.

Within yet other embodiments ISMs having chemical and temperaturesensors can be utilized to monitor skin temperature, skin integrity,and/or the presence of an infection or a developing infection.

In summary, ISMs having a wide variety of sensors may be placed onand/or within the external orthopedic hardware described herein, inorder to provide “real time” information and feedback to a health careprovider (or a surgeon during a surgical procedure), to detect properplacement, anatomy, alignment, mobility/immobility (of injured tissuesand related joints), forces exerted on surrounding tissues, and todetect the strain encountered in an surgical procedure. For example, theexternal orthopedic hardware provided herein (e.g., casts, splints,braces, tensors, slings and supports) can have one or more ISMs whichcontain a combination of contact sensors, strain gauge sensors, pressuresensors, fluid pressure sensors, position sensors, accelerometers, shocksensors, rotation sensors, vibration sensors, tilt sensors, pressuresensors, tissue chemistry sensors, tissue metabolic sensors, mechanicalstress sensors and temperature sensors. ISMs can be placed at a densityof greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensorsper square centimeter or at a density of greater than 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or greater than 10 sensors per cubic centimeter. Withineither of these embodiments there can be less than 50, 75, 100, or 100sensors per square centimeter, or per cubic centimeter.

The above described ISMs may be continuously or intermittently monitoredin order to provide ‘real-world’ activity (of affected limbs. jointsetc.), fixation, mobility/immobility, healing, progressiverehabilitation and function and to collect and compare procedureperformance data over time, to evaluate patient activity, and to betterunderstand the conditions which implants are exposed to in the realworld.

B.8.B. Internal Orthopedic Hardware: K-Wires, Pins, Screws, Plates, andIntramedullary Devices

Within other aspects of the invention, ISMs are provided forincorporation into a wide variety of internal orthopedic devices. Forexample, Kirschner-wires or “K-wires”, pins, screws, plates, andintramedullary devices (e.g., rods and nails) used to repair fractured,dislocated and injured musculoskeletal tissues.

B.8.B.1. Pins

Pins are a common orthopedic device, and are typically utilized as a wayto stabilize bone fractures. One of the most common pins is theSteinmann Pin (also sometimes referred to as Intramedullary Pins or IMPins), which is driven through the skin and into the bone in order toprovide an anchor or support for the patient's fracture. Most commonly,pins have either a two-sided (chisel) or a three-sided trocar tip (whichis better suited to penetrating cortical bone). FIG. 27 illustrates oneembodiment wherein an ISM is placed on or within several pins.

Within one embodiment of the invention, Pins are provided with an ISMhaving one or more pressure sensors. The pressure sensors can bedistributed on, or within, the Pin at specific or randomized locations.Within certain embodiments the ISM may be concentrated on the cuttingend of the Pin. The ISM pressure sensors can be useful during placementand removal (if necessary) of the Pin, during movement through differenttissues [e.g., in order to determine soft tissue (low pressure),cortical bone (high pressure), cancellous bone (moderate pressure),marrow (low pressure), fracture planes (little to no pressure)—in orderto assist in detection, placement and anatomical location].

ISM pressure sensors can also be useful after placement of a Pin. Forexample, detection of increased pressure on the Pin, or across thefracture plane, can indicate the potential for stress shielding (e.g., areduction of bone density due to too much stress being borne by theimplanted Pin and not enough being borne by the bone tissue) and/orincreased potential for the Pin to bend, crack or break. Detection ofincreased pressure on the Pin in soft tissues can indicate the potentialfor the development of compartment syndrome. Detection of reducedpressure on the Pin, or across the fracture plane, can indicate thepotential for non-union of the fracture (early in the healing process)or the successful completion of healing (later in the healing processwhen the bone has assumed normal support functions). Unequal and/orunbalanced pressures on the Pin, or across the fracture plane, can be asign of poor alignment, shifting, and/or the application of torque onthe healing bone. In all cases, identifying the presence of improperpressure forces across the fracture plane can allow for preemptiveintervention to better stabilize the injury and prevent further damageto the bone.

Within other embodiments Pins are provided with an ISM havingaccelerometers (and strain gauges). ISMs having accelerometers (andstrain gauges) can be distributed on, or within the Pin at specific orrandomized locations. However, within certain embodiments the ISM may beconcentrated on the cutting end of the Pin. The ISM accelerometersensors can be useful during placement and removal (if necessary) of thePin by being able to detect movement through different tissues; they canalso assist with achieving correct anatomical placement, alignment andimaging intraoperatively.

ISM accelerometers and strain gauges can also be useful after insertionof a Pin. For example, they can be utilized post-operatively to monitoralignment, stability, fragment mobility/immobility, healing, patientactivities, stresses across the fracture, and related jointimmobilization (or lack thereof).

Within another embodiment of the invention, Pins are provided with oneor more ISMs having one or more position sensors/location markersensors. The ISM containing position sensors/location marker sensors canbe distributed on, or within the Pin at specific or randomizedlocations. Within certain embodiments the ISM may be concentrated on thecutting end of the Pin. The position sensors/location marker sensors canbe useful during placement and removal (if necessary) of the Pin, duringmovement through different tissues (e.g., in order to determine softtissue, cortical bone, cancellous bone, marrow, fracture planes—toassist in detection and determination of anatomical location, fractureanatomy, and correct post-surgical alignment), as well as in imaging andfunctional monitoring after placement.

ISM position sensors/location marker sensors can also be useful afterplacement of a Pin. For example, they can be utilized to monitor healinganatomy, and compare changes in location over time (e.g., post-surgery).They can also be utilized to monitor alignment, shifting and migration,to confirm joint immobilization, and to detect wire bending and/orbreakage.

Within yet other embodiments of the invention, Pins are provided withISMs having temperature sensors and or chemical sensors. Briefly,temperature and/or chemical sensors can be utilized to monitor skin andtissue temperature, skin and tissue integrity, and/or the presence of aninfection or a developing infection [e.g., bone infections(Osteomyelitis), and/or tissue necrosis].

As should be readily evident given the disclosure provided herein, thePins of the present invention can have one or more ISMs having acombination of one or more contact sensors, strain gauge sensors,pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors. Sensors canbe placed at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per square centimeter or at a density of greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per cubiccentimeter. Within either of these embodiments there can be less than50, 75, 100, or 100 sensors per square centimeter, or per cubiccentimeter.

The above ISMs containing sensors may be continuously or intermittentlymonitored in order to provide a ‘real-world’ assessment of alignment ofthe bone, to assist in detecting mobility/immobility of the fracture(and associated joints), to monitor healing and the development ofcomplications, to collect and compare procedure performance data overtime, to evaluate patient function, and to better understand theconditions which implants are exposed to in the real world.

B.8.B.2. Kirschner Wires

Kirschner wires (or K-wires) are sharpened, sterilized steel wires thatwere originally developed by Martin Kirschner in 1909. K-wires camealong after Steinmann Pins, when Dr. Kirschner recognized that largerpins caused more bone damage, as well as infection. Dr. Kirschnercreated his own device made of chrome piano wire to provide bettertension when aligning fractured fragments of bone into place. Hence, theprinciple difference between wires and pins is one of size. Smallerdiameters are referred to as wires and larger diameters are referred toas pins. Although there is no standardized definition of diameter cutoff, typically pins are between 1.5 mm and 6.5 mm in diameter, whereinK-wires are 0.9 to 1.5 mm in diameter.

K-wires are typically made of metal (e.g., stainless steel or nitinol),and come in a variety of sizes, diameters and lengths. They are commonlyutilized to hold together bone fragments, to provide an anchor forskeletal fixation, or as a guide for screw placement, and are oftendriven into bone using a power or hand drill. FIG. 28 illustrates oneembodiment wherein an ISM is placed on and/or within several K-wires.

Within one embodiment of the invention K-wires are provided with an ISMhaving one or more pressure sensors. The ISM can have pressure sensorscan be distributed on, or within the K-wire at specific or randomizedlocations. Within certain embodiments the ISM may be concentrated on thecutting end of the K-wire. The ISM pressure sensors can be useful duringplacement and removal (if necessary) of the K-wire, during movementthrough different tissues [e.g., in order to determine soft tissue (lowpressure), cortical bone (high pressure), cancellous bone (moderatepressure), marrow (low pressure), fracture planes (little to nopressure)—in order to assist in detection, placement and anatomicallocation].

ISM pressure sensors can also be useful after placement of a K-wire. Forexample, detection of increased pressure on the K-wire, or across thefracture plane, can indicate the potential for stress shielding and/orincreased potential for the Pin to bend, crack or break. Detection ofincreased pressure on the K-wire in soft tissues can indicate thepotential for the development of compartment syndrome. Detection ofreduced pressure on the K-wire, or across the fracture plane, canindicate the potential for non-union of the fracture (early in thehealing process) or the successful completion of healing (later in thehealing process when the bone has assumed normal support functions).Unequal and/or unbalanced pressures on the K-wire, or across thefracture plane, can be a sign of poor alignment, shifting, and/or theapplication of torque on the healing bone. In all cases, identifying thepresence of improper pressure forces across the fracture plane can allowfor preemptive intervention to better stabilize the injury and preventfurther damage to the bone.

Within other embodiments K-wires are provided with an ISM havingaccelerometers (and strain gauges). Similar to ISMs having pressuresensors, ISMs having accelerometers (and strain gauges) can bedistributed on, or within the K-wire at specific or randomizedlocations. However, within certain embodiments the ISM may beconcentrated on the cutting end of the K-wire. The ISM accelerometersensors can be useful during placement and removal (if necessary) of theK-wire by being able to detect movement through different tissues; theycan also assist with achieving correct anatomical placement, alignmentand imaging intraoperatively.

ISM accelerometers and strain gauges can also be useful after insertionof a K-wire. For example, they can be utilized post-operatively tomonitor alignment, stability, fragment mobility/immobility, healing,patient activities, stresses across the fracture, and related jointimmobilization (or lack thereof).

Within another embodiment of the invention, K-wires are provided withone or more ISMs having one or more position sensors/location markersensors. The ISMs having position sensors/location marker sensors can bedistributed on, or within the K-wire at specific or randomizedlocations. Within certain embodiments the ISM may be concentrated on thecutting end of the K-wire. The position sensors/location marker sensorscan be useful during placement and removal (if necessary) of the K-wire,during movement through different tissues (e.g., in order to determinesoft tissue, cortical bone, cancellous bone, marrow, fracture planes—toassist in detection and determination of anatomical location, fractureanatomy, and correct post-surgical alignment), as well as in imaging andfunctional monitoring after placement.

ISM position sensors/location marker sensors can also be useful afterplacement of a K-wire. For example, they can be utilized to monitorhealing anatomy, and compare changes in location over time (e.g.,post-surgery). They can also be utilized to monitor alignment, shiftingand migration, to confirm joint immobilization, and to detect wirebending and/or breakage.

Within yet other embodiments of the invention, K-wires are provided withISMs having temperature sensors and or chemical sensors. Briefly,temperature and/or chemical sensors can be utilized to monitor skin andtissue temperature, skin and tissue integrity, and/or the presence of aninfection or a developing infection [e.g., bone infections(Osteomyelitis), and/or tissue necrosis].

As should be readily evident given the disclosure provided herein, theK-wires of the present invention can have one or more ISMs having acombination of one or more contact sensors, strain gauge sensors,pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors. Sensors canbe placed at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per square centimeter or at a density of greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per cubiccentimeter. Within either of these embodiments there can be less than50, 75, 100, or 100 sensors per square centimeter, or per cubiccentimeter.

The above ISMs can be continuously monitored in order to provide a‘real-world’ assessment of alignment of the bone, to assist in detectingmobility/immobility of the fracture (and associated joints), to monitorhealing and the development of complications, to collect and compareprocedure performance data over time, to evaluate patient function, andto better understand the conditions which implants are exposed to in thereal world.

B.8.B.3. Screws

Bone screws are one of the most common devices used in orthopedicsurgery. In 1850 two French surgeons (Cucel and Rigaud) are creditedwith performing the first internal fixation procedure with 2transcutaneous screws fastened by string. Subsequently, in 1866 Germansurgeon Carl Hansmann performed an internal plate fixation using aremovable steel plate and nickel-plated screws. It wasn't until the1940s however that surgeons began to advocate for screws that werespecifically designed for human bone. For example, Belgian surgeonRobert Danis proposed three key design features for bone screws: 1) aratio of exterior diameter to core diameter of 3:2, not 4:3 as wastypical to common metal screws; 2) a reduction of thread surface area toone-sixth that of metal screws (because bone is not as strong as metal);and 3) a buttress thread design to replace standard V-shaped threads,hence enhancing holding power.

Bone screws now come in a variety of sizes and shapes. They may becomposed of a wide variety of polymers, metals and metal alloys, and avariety of shapes, configurations and sizes (e.g., polyaxial screws,monoaxial screws, locking screws, self-drilling screws, self-lockingscrews, self-tapping screws, cannulated screws, screws with alow-profile, hex heads, etc.).

In addition, screws may be designed for a particular purpose. Forexample, cortical screws (for use in cortical bone) are typically fullythreaded and require a tap to cut threads prior to insertion.

Cancellous screws (which are designed for cancellous bone) are typicallyself-tapping screws with a relatively thin core and wide deep threads.They may be fully threaded (e.g., ideally for use in fastening devicessuch as plates into the metaphyseal or epiphyseal areas of bone), orpartially threaded (they may be utilized for an area far from thecortex, but do not, however, have as much holding power).

In addition to more common screw types (such as the cancellous andcortical screws), there are a large number of specialty bone screws. Forexample, dynamic hip screws (“DHS”) are a type of orthopedic implantcomposed of a plate, along with different types of bone screws that arespecifically designed for certain types of hip fractures (typicallyintertrochanteric fractures). More specifically, a DHS side plate isaligned to a joint (e.g., a broken femoral head), and a hole is preparedutilizing a reamer. The sideplate, lag screw and cortical screws areattached to the bone. The idea of this implant is to cause dynamiccompression of the femur and the femoral head, causing them to movealong one plane (thereby hopefully allowing the native femur to undergoremodeling and proper fracture healing).

Other specialty bone screws include the Herbert screws and Acutrakscrews which are cannulated and threaded at both ends, and typicallyutilized in fractures of small articular bones (e.g., carpal andscaphoid fractures). Interference screws can be specifically designedfor certain procedures (e.g., soft tissue and bone-tendon-bone grafts),and are commonly comprised of polymers (e.g., PLDLA) and othercomponents (e.g., Tri-Calcium Phosphate), (see, e.g., U.S. Patent Pub.No. 2009/0198288).

Within one embodiment of the invention ISMs having pressure sensors areprovided on or within a bone screw (e.g., cancellous or cortical screw,interference screw, or dynamic hip screw). The ISM can be positionedwithin specific locations (e.g., at the point and/or head), ordistributed throughout the screw. They can be utilized to assist inimplanting the screw by detecting various tissue types (e.g.,cancellous/cortical bone and bone marrow), detecting fracture planes,and assisting in the determination of anatomy and location. They canalso be utilized to prevent accidental placement (e.g., into thearticular cartilage; i.e. the pressure would drop from higher to lowerwhen the screw moved from cortical bone into the articular cartilage).For example, detection of increased pressure on the screw, or across thefracture plane, can indicate the potential for stress shielding and/orincreased potential for the screw to bend, crack or break. Detection oftwo much pressure on a DHS can be an indicator of impaction (with therisk of bone shortening). Detection of reduced pressure on the screw, oracross the fracture plane, can indicate the potential for non-union ofthe fracture (early in the healing process) or the successful completionof healing (later in the healing process when the bone has assumednormal support functions; monitoring this can be helpful in determiningthe timing of ambulation). Unequal and/or unbalanced pressures on thescrew, or across the fracture plane, can be a sign of poor alignment,shifting, and/or the application of torque on the healing bone. In allcases, identifying the presence of improper pressure forces across thefracture plane can allow for preemptive intervention to better stabilizethe injury and prevent further damage to the bone.

Within another embodiment bone screws are provided with ISMs havingaccelerometers (and strain gauges). Similar to ISMs having pressuresensors, ISMs having accelerometers (and strain gauges) can bedistributed on, or within the bone screw at specific or randomizedlocations. However, within certain embodiments the ISM may beconcentrated on the point or head of the screw. The ISM accelerometersensors can be useful during placement and removal (if necessary) of thescrew by being able to detect movement through different tissues; theycan also assist with achieving correct anatomical placement, alignmentand imaging intraoperatively.

ISM accelerometers and strain gauges can also be useful after insertionof a screw. For example, they can be utilized post-operatively tomonitor alignment, stability, fragment mobility/immobility, healing,patient activities, stresses across the fracture, and related jointimmobilization (or lack thereof).

Within another embodiment of the invention, screws are provided with oneor more ISMs having position sensors/location marker sensors. The ISMshaving position sensors/location marker sensors can be distributed on,or within the screw at specific or randomized locations. Within certainembodiments the ISM may be concentrated on the cutting end of the screw.The ISM position sensors/location marker sensors can be useful duringplacement and removal (if necessary) of the screw, during movementthrough different tissues (e.g., in order to determine soft tissue,cortical bone, cancellous bone, marrow, fracture planes—to assist indetection and determination of anatomical location, fracture anatomy,and correct post-surgical alignment), as well as in imaging andfunctional monitoring after placement.

ISM position sensors/location marker sensors can also be useful afterplacement of a bone screw. For example, they can be utilized to monitorhealing anatomy, and compare changes in location over time (e.g.,post-surgery). They can also be utilized to monitor alignment, shiftingand migration, to confirm joint immobilization, and to detect screwbending and/or breakage. Importantly, bone screws with positionsensors/location markers can be utilized to detect movement (e.g.,‘backing out’) of the screw before serious complications arise. In DHS,lack of movement of the screw in the tunnel is a sign of non-union or ofadvancement of the screw into the articular cartilage, while excessivemovement of the screw in the tunnel is inactive of shortening (andimpaction). Similarly, for screws that are utilized with plates, a bonescrew with ISMs containing sensors can be utilized to detect platemovement, and allow intervention prior to serious complications.

Within yet other embodiments of the invention bone screws are providedwith one or more ISMs having temperature sensors and or chemicalsensors. Briefly, temperature and/or chemical sensors can be utilized tomonitor mineralization, tissue health, bleeding, tissue temperature,tissue health (such as avascular necrosis of the hip), and/or thepresence of an infection or a developing infection [e.g., boneinfections (Osteomyelitis), and/or tissue necrosis].

In a particularly preferred embodiment, a dynamic hip screw is providedwith an ISM containing multiple sensors located in the “shaft” of thescrew (see FIGS. 29A and 29B). For an ISM collecting mechanical data(position, motion, vibration, rotation, shock, tilt, steps), theimplanted ISM sensors (accelerometers, position sensors, pedometers)have the advantage of not requiring either direct physical contact withthe surface of the device or with patient tissues; only a secure andimmobile attachment within the dynamic hip screw is needed. In thispreferred embodiment, the ISM containing multiple mechanical sensors (asdescribed above) is placed within the internal canal of the dynamic hipscrew; a location that provides more than enough space to insert andseal an ISM with multiple sensor functions and battery capability.Furthermore, the motion of the screw as the hip joint goes through itsrange of motion during normal activities (such as walking) can provideopportunities to power the ISM.

As should be readily evident given the disclosure provided herein, thebone screws of the present invention can have one or more ISMs having acombination of one or more contact sensors, strain gauge sensors,pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors. Sensors canbe placed at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per square centimeter or at a density of greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per cubiccentimeter. Within either of these embodiments there can be less than50, 75, 100, or 100 sensors per square centimeter, or per cubiccentimeter.

The above ISM sensors may be continuously monitored in order to providea ‘real-world’ assessment of the alignment of the bone, to assist indetecting mobility/immobility of the fracture (and associated joints),to monitor healing and the development of complications, to collect andcompare procedure performance data over time, to evaluate patientfunction, and to better understand the conditions which implants areexposed to in the real world.

B.8.B.4. Plates

Orthopedic plates (also referred to as ‘fixation plates’ and ‘traumaplates’) have been utilized to fix fractures for over a hundred years.The first metal plate was introduced by Dr. Lane in 1895 for theinternal fixation of fractures.

Fixation plates now come in a wide variety of shapes and sizes, for avariety of specific indications. Representative examples include: 1) theDHS sideplate shown in FIG. 29A for the fixation of fractures at or nearthe femoral head; 2) DC plates (typically used for the ulna and radiusrepairs); 3) Buttress plates (e.g., for the repair of comminuted tibialfractures); L-Buttress plates (for complicated surgeries); 4) ClavicleHook plates; 5) Clover Leaf plates; 6) Condylus Humerus Bone plates; and7) Humerus and Tibial Compression plates (too name a few). Typicallyplates are comprised of metals such as stainless steel or titanium. FIG.29 illustrates an embodiment wherein an ISM is placed on or within arepresentative fixation plate.

Within one embodiment of the invention an ISM having pressure sensorsare provided on or within a plate. The ISM having pressure sensors canbe positioned within specific locations (e.g., on the bone or tissuesurface, around screw holes), or distributed throughout the plate. Theycan be utilized to assist in implanting the plate by detecting adherenceto or contact with bone (e.g., for malleable plates like reconstructionplates), and or movement through tissue or bone during placement (e.g.on the chisel of blade plates). They can also be useful after placement.For example, detection of increased pressure can indicate the potentialfor stress shielding or the potential for bending cracking or fractureof the plate. Detection of increased pressure on the tissue surfacecould be an indicator of compartment syndrome. Detection of a rapidchange in pressure can indicate plate breakage. Detecting a slowdecrease in pressure can indicate that healing is occurring and canassist in decisions on weight bearing and rehabilitation. Monitoring thepressure around the screw holes can assist with appropriate tighteningduring placement; later it can be used to detect “backing out” of thescrews or other complications such as breakage.

Within another embodiment plates are provided with one or more ISMshaving accelerometers (and strain gauges). Such ISMs can be distributedon, or within the plate at specific or randomized locations. Withincertain embodiments they may be concentrated on specific locations(e.g., on both the bone and tissue surface, at the ends, and/or aroundscrew holes). The ISM accelerometers can be useful during placement andremoval (if necessary) of the plate, for proper alignment, fit, contour,blade placement and imaging.

ISM accelerometers and strain gauges can also be useful after placementof a plate. For example, they can be utilized post-operatively tomonitor alignment, stability, healing, patient activities, stressesacross the fracture, rotation, bending, breakage, platemovement/slippage, and joint immobilization (or lack thereof).

Within another embodiment of the invention, plates are provided with oneor more ISMs having position sensors/location marker sensors. Such ISMscan be distributed on, or within the plate at specific or randomizedlocations. Within certain embodiments they may be concentrated onspecific locations (e.g., on both the bone and tissue surface, plateends, and/or around screw holes). The ISM position sensors/locationmarker sensors can be useful during placement and removal (if necessary)of the plate, during movement through different tissues (for bladeplates), to monitor alignment and molding to the bone surface, and in animaging function after placement.

ISM position sensors/location marker sensors can also be useful afterplacement of a plate. For example, they can be utilized to monitorhealing anatomy, and compare changes in location over time (e.g.,post-surgery). They can also be utilized to monitor alignment, shiftingand migration, to confirm joint immobilization, and to detect platebending and/or breakage. Importantly, plates with positionsensors/location markers can be utilized to detect movement (e.g.,‘backing out’) of the screw before serious complications arise.

Within yet other embodiments of the invention plates are provided withan ISM having temperature sensors and or chemical sensors. Briefly,temperature and/or chemical sensors can be utilized to monitormineralization, galvanic corrosion, tissue health, bleeding, tissuetemperature, tissue integrity, and/or the presence of an infection or adeveloping infection [e.g., bone infections (Osteomyelitis), and/ortissue necrosis].

As should be readily evident given the disclosure provided herein, theplates of the present invention can have one or more ISMs having acombination of one or more contact sensors, strain gauge sensors,pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors. Sensors canbe placed at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per square centimeter or at a density of greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per cubiccentimeter. Within either of these embodiments there can be less than50, 75, 100, or 100 sensors per square centimeter, or per cubiccentimeter.

The above ISMs may be continuously monitored in order to provide a‘real-world’ assessment of alignment of the bone, to assist in detectingmobility/immobility of the fracture (and associated joints), to monitorhealing and the development of complications, to collect and compareprocedure performance data over time, to evaluate patient function, andto better understand the conditions which implants are exposed to in thereal world.

B.8.B.5. Intramedullary Fixation: Rods and Nails

Intramedullary rods and nails are long metal rods which are implantedinto the medullary cavity of a fractured long bone (e.g., a femur,humerus, or tibia), thereby providing greater stability and support tothe bone during healing.

Intramedullary fixation of long bone fractures has been around forcenturies. The earliest recorded evidence is that of an anthropologistwho in the 16^(th) century travelled to Mexico and witnessed Aztecphysicians placing wooden sticks into the medullary canals of patientswith long bone non-unions. Ivory and metal was also utilized in earlytreatments, although the rate of infection and complications was veryhigh. During the 1900s, Gerhard Kuntscher believed that the same sciencebehind the Smith-Petersen nails might work for diaphyseal fractures, andthus he developed his ‘marrow nail’.

Since that time the science of intramedullary devices (e.g., rods andnails) has expanded greatly. Today there are a wide variety ofintramedullary rods or nails which are designed for specificapplications, including for example, interlocking nails, Küntschernails, Ender's nail, Grosse-Kempf (GK) nails, Gamma nails, and Rushnails.

As noted above, the present invention provides intramedullary rods andnails (also referred to as “intramedullary devices”) which have ISMscontaining a variety of sensors. FIG. 30A illustrates a representativeflexible nail or rod having an ISM for intramedullary fixation. FIG. 30Billustrates the rod or nail within the humerus.

Within one embodiment of the invention ISMs having pressure sensors areprovided on or within an intramedullary rod or nail device. The ISMs canbe positioned within specific locations (e.g., at the ends, on or aroundscrew holes in interlocking nails, or contained within the shaft of therod or nail), or distributed throughout the intramedullary device. Theycan be utilized to assist in implanting the intramedullary nail or roddevice by detecting soft tissues, bone and marrow, and or movementthrough tissue or bone during placement. They can also be useful afterplacement. For example, detection of increased pressure can indicate thepotential for stress shielding or the potential for bending cracking orfracture of the rod or nail. Detection of a rapid change in pressure canindicate rod or nail breakage. Detecting a slow decrease in pressure canindicate that healing is occurring and can assist in decisions on weightbearing and rehabilitation. Monitoring the pressure around the screwholes can assist with appropriate tightening during placement; later itcan be used to detect “backing out” of the screws or other complicationssuch as breakage.

Within another embodiment intramedullary devices are provided with ISMshaving accelerometers (and strain gauges). Such ISMs can be distributedon, or within the intramedullary device at specific or randomizedlocations. Within certain embodiments they may be concentrated onspecific locations (e.g., on both ends, and/or around screw holes, orcontained within the shaft of the rod or nail). The accelerometers canbe useful during placement and removal (if necessary) of theintramedullary device, during movement through different tissues, andfor proper placement, fit, alignment, movement and imaging.

ISM accelerometers and strain gauges can also be useful after placementof an intramedullary device. For example, they can be utilizedpost-operatively to monitor alignment, stability, healing, patientactivities, stresses across the fracture, axial loading, and rod/nailrotation, bending, breakage or slippage.

Within another embodiment of the invention intramedullary devices areprovided with one or more ISMs having one or more positionsensors/location marker sensors. The ISMs can be distributed on, orwithin, the intramedullary device at specific or randomized locations.Within certain embodiments they may be concentrated on specificlocations (e.g., at the ends, and/or around screw holes, or containedwithin the shaft of the rod or nail). The ISM position sensors/locationmarker sensors can be useful during placement and removal (if necessary)of the intramedullary device, during movement through different tissues(soft tissue, cortical bone cancellous bone, marrow, through thefracture plane), to monitor alignment, and in an imaging function afterplacement.

ISM position sensors/location marker sensors can also be useful afterplacement of an intramedullary device. For example, they can be utilizedto monitor healing anatomy, and compare changes in location over time(e.g., post-surgery). They can also be utilized to monitor alignment,shifting and migration, to confirm fracture immobilization, and todetect rod/nail bending and/or breakage. Importantly, intramedullarydevices with position sensors/location markers can be utilized to detectmovement, slippage and alignment changes before serious complicationsarise.

Within yet other embodiments of the invention intramedullary devices areprovided with and ISM having temperature sensors and or chemicalsensors. Briefly, temperature and/or chemical sensors can be utilized tomonitor mineralization, tissue health, bleeding, tissue temperature,tissue integrity, and/or the presence of an infection or a developinginfection [e.g., bone infections (Osteomyelitis), and/or tissuenecrosis].

In a particularly preferred embodiment, an intramedullary rod or nail isprovided with an ISM containing multiple sensors located in the “shaft”of the shaft of the rod or nail. For an ISM collecting mechanical data(position, motion, vibration, rotation, shock, tilt, steps), theimplanted ISM sensors (accelerometers, position sensors, pedometers)have the advantage of not requiring either direct physical contact withthe surface of the device or with patient tissues; only a secure andimmobile attachment within the intramedullary rod or nail is needed. Inthis preferred embodiment, the ISM containing multiple mechanicalsensors (as described above) is placed within the internal canal of theintramedullary rod or nail; a location that provides more than enoughspace to insert and seal an ISM with multiple sensor functions andbattery capability. Furthermore, the motion of the intramedullary rod ornail as the lower limb goes through its range of motion during normalactivities (such as walking) can provide opportunities to power the ISM.

As should be readily evident given the disclosure provided herein, theintramedullary devices of the present invention can have one or moreISMs having a combination of one or more contact sensors, strain gaugesensors, pressure sensors, fluid pressure sensors, position sensors,accelerometers, shock sensors, rotation sensors, vibration sensors, tiltsensors, pressure sensors, tissue chemistry sensors, tissue metabolicsensors, mechanical stress sensors and temperature sensors. Sensors canbe placed at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per square centimeter or at a density of greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 sensors per cubiccentimeter. Within either of these embodiments there can be less than50, 75, 100, or 100 sensors per square centimeter, or per cubiccentimeter.

The above sensors may be continuously monitored in order to provide a‘real-world’ assessment of the alignment of the bone, to assist indetecting mobility/immobility of the fracture (and associated joints),to monitor healing and the development of complications, to collect andcompare procedure performance data over time, to evaluate patientfunction, and to better understand the conditions which implants areexposed to in the real world.

B.8.B.6. General Considerations

In summary, one or more ISMs having a combination of one or more sensorsmay be placed on and/or within internal orthopedic hardware in order toprovide “real time” information and feedback to the surgeon during andafter the procedure, to detect proper device placement, to achieveproper fracture reduction and alignment during and after surgery, and todetect and monitor the forces the implant will be subjected to in theactivities of daily life.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of sensorsplaced on an orthopedic hardware device, or an orthopedic hardwaresurgical delivery device are provided in U.S. Provisional No.62/017,106, which is hereby incorporated by reference in its entirety.

B.9. Medical Polymers

Within another aspect of the invention, ISMs as described herein areprovided for use in one or more polymers. “Polymer” refers to amacromolecule, typically in excess of 1,000 g/mol, or in excess of 5,000g/mol molecular weight, or in excess of 10,000 g/mol, which comprises aplurality of repeating units that are present as part of the backbone ofthe polymer, the plurality typically in excess of 10, or in excess of20, or in excess of 50.

Polymers may be composed of synthetic materials (e.g., silicone,polyurethane and rubber), composed of non-synthetic components (e.g.,collagen, fibrin, hyaluronic acid, chitosan, and harvested grafts forbypass), or some combination of these (e.g., artificial blood vesselshaving a synthetic polymer scaffold, and naturally occurring cells(e.g., fibroblasts) which produce matrix materials for the vessel (e.g.,collagen). Representative examples of polymers include polyester,polyurethanes, silicones, epoxy resin, melamine formaldehyde resin,acetal, polyethyelene terephthalate, polysulphone, polystyrene,polyvinyl chloride, polyamide, polyolefins, polycarbonate, polyethylene,polyamides, polimides, polypropylene, polytetrafluoroethylene, ethylenepropylene diene rubber, styrenes (e.g., styrene butadiene rubber),nitriles (e.g., nitrile rubber), hypalon, polysulphide, butyl rubber,silicone rubber, cellulose, chitosan, fibrinogen, collagen, hyaluronicacid, PEEK, PTFE, PLA, PLGA, PCL and PMMA.

The polymer containing sensors of the present invention are preferablysuitable for medical applications (e.g., medical devices and/or implantsas described herein), and hence are preferably sterile, non-pyrogenic,and/or suitable for use and/or implantation into humans. However, withincertain embodiments of the invention the polymer can be made in anon-sterilized environment (or even customized or “printed” for anindividual subject), and sterilized at a later point in time.

B.9.A. Polymers

A wide variety of polymers can be utilized with the ISMs describedherein. Examples include polyester, polyurethane, silicone, epoxy resin,melamine formaldehyde resin, acetal, polyethyelene terephthalate,polysulphone, polystyrene, polyvinyl chloride, polyamide, polycarbonate,polyethylene, polypropylene, polytetrafluoroethylene, ethylene propylenediene rubber, polyurethane rubber, styrene butadiene rubber, nitrilerubber, hypalon, polysulphide, butyl rubber, and silicone rubber. Thepolymer may be classified by whether it is synthetic or non-synthetic.In addition, or alternatively, it may be classified as beingbiodegradable or non-biodegradable. In one embodiment, the polymer is asynthetic biodegradable polymer, for example, a co-polymer of lactideand glycolide. In another embodiment, the polymer is a syntheticnon-biodegradable polymer, such as polyvinyl chloride. In anotherembodiment, the polymer is a non-synthetic, i.e., a natural occurringpolymer that is biodegradable, such as collagen, fibrinogen, and/orhyaluronic acid. In another aspect, the polymer is a non-syntheticpolymer that is non-biodegradable, e.g., cellulose and chitin. Some ofthese, as well as additional examples, are discussed further below.

In one embodiment ISMs may be contained in a polymer such as apolyester. Polyesters contain repeating ester groups separated byaliphatic or aromatic groups. Polyesters may be formed by reactionbetween a di-acid (e.g., adipic acid, phthalic acid) and a di-alcohol(e.g., ethylene glycol, butylene glycol), or reactive equivalentsthereof. The polyester may be biodegradable, such as polylactic acid(PLA), poly (lactic-co-glycolic) acid (PLGA), and polycaprolactone(PCL).

In another embodiment ISMs may be contained in a polymer such as apolyether, optionally including other repeating units. For example, thepolymer may be a polyetherimide, having both repeating ether and imidegroups. As another example, the polymer may be a polyethersulfone, withrepeating ether and sulfone groups.

The polymer may be characterized in terms of its thermal properties. Forexample, in one embodiment the polymer is a thermoplastic. Athermoplastic becomes plastic (i.e., fluid) upon heating and hardensupon cooling and is able to repeat this phase change multiple times inresponse to changes in temperature. Examples of thermoplastics includePET, polysulphone, polystyrene, UPVC, polyamides, polycarbonates,polyethylene, polypropylene and PTFE. In another embodiment the polymeris a thermoset. A thermoset is does not become fluid upon heating, butinstead retains it hardened form even at elevated temperature. Examplesof thermosets include epoxy and phenolics.

In another embodiment ISMs may be contained in a polymer such as aphenolic. Many phenolic polymers are thermoset. Phenolic resins aretypically formed between a phenol and formaldehyde, and is sometimesreferred to a phenol formaldehyde resin. Novolacs are phenolics madewith a formaldehyde to phenol molar ratio of less than one, whileresoles are phenolics made with a formaldehyde to phenol ratio ofgreater than one (usually around 1.5).

The polymer may be an epoxy. Many epoxy polymers are thermoset. Hardenedepoxy resins are formed between a polyepoxide compound (often adi-epoxide) and a curing agent such as a poly-hydroxyl or poly-amine. Acommon epoxy resin is the reaction product between epichlorohydrin andbisphenol A to form diglycidyl ethers of bisphenol A. A common curingagent is triethylenetetramine. Epoxy resins may also be thermally cured.Epoxy resins are tough and resistant to many environments, making themuseful components of many medical polymers.

ISMs may also be incorporated in to a polymer such as a polyolefin. Manypolyolefin polymers are thermoplastic. Exemplary polyolefins arepolyethylene (PE) and polypropylene (PP). Polyolefins are commerciallyavailable in a wide range of molecular weights, and different molecularweights have different properties and different applications. Forexample, ultra-high molecular weight PE can be used to prepare loadbearing materials in total joint replacements.

In one aspect, the invention utilizes ISMs in polyethylene, for examplecrosslinked polyethylene (XLPE) and ultra high molecular weightpolyethylene (UHMWPE) which may be crosslinked. The crosslinkedpolyethylene may be so-called highly-crosslinked polyethylene. (See,e.g., Lachiewicz et al. “The use of highly cross-linked polyethylene intotal knee arthroplasty” J Am Acad Orthop Surg. 2011 March;19(3):143-51, and Journal of the AAOS (Vol. 16, Supplement 1, 2008),providing the proceedings of a symposium titled 2007 AAOS/NIH Osteolysisand Implant Wear: Biological, Biomedical Engineering, and SurgicalPrinciples, and Glyn-Jones et al. “The creep and wear of highlycross-linked polyethylene: a three-year randomized controlled trialusing radiostereometric analysis” J Bone Joint Surg Br. 2008 May;90(5):556-61, and Hodrick et al. “Highly crosslinked polyethyelene issafe for use in total knee arthroplasty” Clin Orthop Relat Res. November2008; 466(11): 2806-2812. See also PCT Publication WO2013/124577 andU.S. Pat. Nos. 8,728,379; 8,663,335; 8,653,154; 7,431,874; 7,182,784;and 6,726,727, all of the above of which are incorporated by referencein their entirety.

In another embodiment ISMs may be contained in a polymer such as anacrylonitrile butadiene styrene (ABS), which is typically athermoplastic. As its name suggests, ABS is formed by copolymerizationof the monomers acrylonitrile, butadiene and styrene. ABS may be viewedas a styrene-acrylonitrile copolymer modified by butadiene rubber. ABScombines the resilience of polybutadiene with the hardness and rigidityof polyacrylonitrile and polystyrene. The properties of the ABS polymerdepend to a large extent on the relative amount of each of the monomersused in its preparation. Acrylonitrile tends to impart chemicalresistance, heat stability, increased tensile strength, and agingresistance. Styrene tends to impart gloss and rigidity, and also helpaid is processing the plastic. Butadiene imparts toughness, impactstrength, good low temperature properties.

In another embodiment ISMs may be contained in a polymer such as anethylene vinyl alcohol (EVA, or EVAL or EVOH) copolymer which is formedby copolymerization of ethylene and vinyl acetate, whereupon the acetategroups are hydrolyzed to hydroxyl (alcohol) groups. EVOH isbiocompatible and biodegradable. EVOH is recognized as having excellentbather properties to oxygen, and accordingly is often used as a coatingto provide this desirable function.

In another embodiment ISMs may be contained in a polymer such as afluoroplastic. As used herein, a fluoroplastic refers to a polymer thatis a thermoplastic and which contains carbon-fluorine bonds. Examplesare poly(tetrafluoroethylene), also known as PTFE.

The polymer may be polyvinyl chloride (PVC). PVC comes in two basicgrades: flexible and rigid. The flexible form is typically prepared byincorporation of various additives into the PVC, where exemplaryadditives are plasticizers (e.g., phthalates) and stabilizers. FlexiblePVC is used in many medical applications due to its biocompatibility,transparency, softness, light weight, high tear strength, kinkresistance, and suitability for sterilization. PVC may be chlorinated toincrease its chlorine content, thereby creating CPVC.

In another embodiment ISMs may be contained in a polymer such as apolysulfone (PS). For example, the polymer may be a polyphenylsulfone.Westlake Plastics (Lenni, Pa.) markets medical grade Radel R5500polyphenylsulfone resin. This polymer provides hydrolytic stability,toughness, and good impact strength over a wide temperature range.Recommended sterilization techniques for Radel R5500 include EtO gas,radiation, steam autoclaving, dry heat and cold sterilization.

In another embodiment ISMs may be contained in a polymer such as apolyether ether ketone (PEEK). An exemplary PEEK polymer is formed byreaction of 4,4′-difluorobenzophenone with the disodium salt ofhydroquinone. PEEK is a semicrystalline, high-temperature (up to 500°F.) engineering thermoplastic that is useful in applications wherethermal, chemical, and combustion properties are important toperformance. PEEK also resists radiation and a wide range of solventsincluding water. With its resistance to hydrolysis, PEEK can withstandboiling water and superheated steam used with autoclave andsterilization equipment at temperatures higher than 482° F., thus makingit useful in the manufacture of many medical parts.

In another embodiment ISMs may be contained in a polymer such as apolycarbonate (PC). For example, Westlake Plastics (Lenni, Pa.) marketsmedical grade Zelux GS polycarbonate which may be sterilized by EtO gasand limited autoclaving sterilization.

In another embodiment ISMs may be contained in a polymer such as apolyimide, such as a polyetherimide. For example, Westlake Plastics(Lenni, Pa.) markets medical grade Tempalux polyetherimide. This polymermaintains its size and shape over a broad temperature range as well astolerates a high amount of stress over extended periods of time.Recommended sterilization techniques for Tempalux include EtO gas,radiation, steam autoclaving, dry heat and cold sterilization.

In another embodiment ISMs may be contained in a polymer such as a onewith repeating oxymethylene units. For example, the polymer may be ahomopolymer of oxymethylene units, which is known polyoxymethylene (POM)or acetal or polyacetal. The term POM will be used to refer tohomopolymers prepared from formaldehyde or equivalent, which may havevarious endgroups to enhance the stability of the homopolymer. When ahigh molecular weight version of the homopolymer is reacted with aceticanhydride, the resulting product is hard, rigid and has high strength. Aversion is sold by du Pont (Wilmington Del.) as their Delrin polymer andadvertised for use in medical products. The polymer may be a copolymerincluding repeating oxymethylene units. For example, formaldehyde may beconverted to 1,3,5-trioxane, which in turn is reacted with a suitableco-monomer such as ethylene oxide or dioxolane. Hostaform from Ticona(now Celanese, Irving, Tex.) and Ultraform from BASF (Florham Park,N.J.) are two examples of commercially available oxymethylenecopolymers. Polyplastics (Taipei, Taiwan) manufactures DURACON POM,which may be used in medical products. TECAFORM MT is a POM manufacturedby Ensinger Inc. (Washington, Pennsylvania) which is particularly suitedfor use as sizing trials in knee, hip and shoulder replacementprocedures.

The polymer may be characterized in terms of its viscoelasticproperties. For example, in one embodiment the polymer is elastic, inwhich case the polymer may be referred to as an elastomer. At ambienttemperatures, elastomers are relatively soft and deformable, i.e., theymay be stretched and will return back to its original shape after thestretching force is removed. One type of elastomer is a rubber, where arubber is typically formed by a process that includes vulcanization.Alternatively, the polymer may be rigid and non-deformable.

In another embodiment ISMs may be contained in a polymer such as apolyurethane. Polyurethanes are formed when a polyol (i.e., apolyhydroxylated compound) reacts with a diisocyanate or a polymericisocyanate when there are suitable catalysts and additives present. Thepolyurethane may be a thermoset, particularly when crosslinkingreactants are used in its preparation. Alternatively, the polyurethanepolymer may be an elastomer. For example, Bayer (Leverkusen, Germany)markets Vulkollan® polymer which is produced by reactingpolyesterpolyols, Desmodur® 15 (one or both of MDI (diphenylmethanediisocyanate) and TDI (toluylene diisocyanate) and glycols attemperatures exceeding 100° C. in a multistage process. Vulkollan®polymer may be formed into parts and is particularly well-suited whenhigh mechanical load bearing and high dynamic load bearing capacity isneeded. Another suitable polyurethane elastomer, also from Bayer, isBaytec® Spray, a material consisting of two liquid, polyurethane-basedcomponents. Baytec® Spray can be used to provide an elastomeric coatingon the surface of a polymer.

In another embodiment ISMs may be contained in a polymer such as a maybe a natural polymer or a synthetic polymer. A natural polymer is foundin nature, where rubber is an example of a natural polymer. A syntheticpolymer is not found in nature but is instead made throughhuman-controlled chemical reactions. Polyurethanes are exemplarysynthetic polymers. Carbohydrates (e.g., cellulose, hyaluronic acid) andpoly(amino acid) (e.g., protein, collagen) are examples of naturalpolymers. Cellulose finds use in, e.g., the manufacture of dialysismembranes. Chitin is a natural polymer, however the syntheticdeacylation of chitin produces the synthetic polymer chitosan.Hyaluronic acid is a natural polymer that finds use in the treatment ofosteoarthritis and other joint disorders.

In another embodiment ISMs may be contained in a polymer such as asynthetic elastomer, also known as a synthetic rubber. There are severalwell-known synthetic elastomers, which are named from the monomer(s)from which they are produced. Those elastomers include cis-polybutadiene(butadiene rubber, BR), styrene-butadiene rubber (SBR),ethylene-propylene monomer (EPM), acrylonitrile-butadiene copolymer(nitrile rubber), isobutylene-isoprene copolymer (butyl rubber),ethylene-propylene-diene monomer (EPDM, where the diene may be, e.g.,butadiene), and polychloroprene (neoprene). In large part thesesynthetic rubbers consist of two or more different monomer units, e.g.,styrene and butadiene, arranged randomly along the molecular chain. EPMand nitrile rubber also consist of a random arrangement of twomonomers-in this case, ethylene and propylene (which form EPM) andbutadiene and acrylonitrile (which form nitrile rubber). Anothersuitable rubber is silicon rubber, which finds widespread use incatheters and other types of medical tubing. Silicon rubber may beprepared by curing a liquid precursor, e.g., with a platinum catalyst,usually at elevated temperature. The glass transition temperatures ofall these polymers are quite low, well below room temperature, so thatall of them are soft, highly flexible, and elastic. The presentdisclosure provides that any one or more of the named synthetic rubbersmay be used in the compositions and methods as identified herein.

Instead of an organic polymer, the polymer or coating may be formed inwhole or in part from a ceramic biomaterial, sometimes referred to as abioceramic. An example of a ceramic biomaterial is hydroxyapatite, whichmay be combined with a binder to create a solid mass or a coating.Suitable binders include collagen, gelatin, and polyvinylalcohol. Asol-gel process may be used to prepare the final product. Other examplesof bioceramics include alumina (Al₂O₃) and zirconia (ZrO₂), tricalciumphosphate (Ca₃(PO₄)₂), and bioglass (Na₂OCaOP₂O₃—SiO). The bioceramicmay be biodegradable (e.g., tricalcium phosphate) or biostable (e.g.,alumina). The bioceramics alumina and zirconia are used in orthopedicsto produce, for example, femoral heads, artificial knees, bone screwsand bone plates, and in dental applications are used to produce crownsand bridges.

The medical polymer may be multi-component. For example, it may be ablend of two or more polymers. As another example, it may be a compositeof organic and inorganic materials. For example, the medical polymer maybe a blend of polyester and a mineral component, or a blend of siliconeand a mineral component.

B.9.B. Bone Cement and other Implantable Materials

As described herein bone cement and other implantable materials can beutilized in a large number of orthopedic procedures (including forexample, hip and knee procedures, spinal procedures and orthopedicprocedures as described herein. Most typically, methylmethacrylates areutilized (e.g., polymethylmethacrylate, or amethylmethacrylate—styrenecopolymer), although other materials can also be utilized.

However, a wide variety of implantable materials can also be utilized(see generally US 2007/0100449). For example, suitable materials includeboth biocompatible polymers, therapeutic agents, and naturally occurringmaterials. Biocompatible polymers may be both bioabsorbable and/ornonbioabsorbable. Typically, the polymers will be synthetics (e.g.,aliphatic polyesters, poly(amino acids), copoly(ether-esters),polyalkylenes oxalates, polyamides, tyrosine derived polycarbonates,poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters,polyoxaesters containing amine groups, poly(anhydrides),polyphosphazenes, poly(propylene fumarate), polyurethane, poly(esterurethane), poly(ether urethane), copolymers of lactide (e.g., D,Llactide), glycolides, caprolactones and blends and copolymers thereof.However, in certain embodiments natural polymers can also be utilized(e.g., fibrin-based materials, collagen-based materials, hyaluronicacid-based materials, glycoprotein-based materials, cellulose-basedmaterials, silks and combinations thereof).

Within certain embodiments of the invention the bone cement orimplantable material may contain a desired agent, compound, or matrix,such as, for example, bone morphogenic protein or “BMP”, bone graftmaterial, and calcium phosphate.

The bone cement and other implantable materials described herein maycontain one or more ISMs having one or more sensors, including forexample, fluid pressure sensors, contact sensors, position sensors,pulse pressure sensors, fluid (e.g., blood, urine, bile) volume sensors,fluid (e.g. blood, urine, bile) flow sensors, air flow sensors,chemistry sensors (e.g., for blood, urine, bile and/or other fluids),metabolic sensors (e.g., for blood, urine, bile and/or other fluids),accelerometers, mechanical stress sensors and temperature sensors.Within certain embodiments the bone cement or implantable material willsensors at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 20sensors per square centimeter; and or sensors a density of greater than1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 20 sensors per cubic centimeter.

B.9.C. Manufacture of Medical Polymers

A polymer may be fabricated into a desired shape for a medical polymerby various methods including extrusion, molding (e.g., injectionmolding, compression molding) thermoforming, electrospinning, andcutting (e.g., stamping, die cutting). During the fabrication process, asensor may be incorporated into the polymer.

For example, the polymer may be fabricated by a thermoforming technique,including vacuum, pressure and mechanical types of thermoforming. Ingeneral, thermoforming refers to a process of converting an initiallyflat thermoplastic sheet into a desired three-dimensional shape, wherethe process includes at least two stages: softening the sheet byheating, followed by forming it in a mold cavity. In vacuumthermoforming, the heated thermoplastic sheet is held in the cavity bymeans of vacuum produced between the sheet and the surface of the moldcavity space. In pressure thermoforming, gas pressure is applied againstthe heated sheet in the direction of the mold cavity, thereby forcingthe sheet against the contours of the cavity. In mechanicalthermoforming, a solid object is pushed against the sheet so that thesheet is forced against the contour of the mold. Upon cooling, thethermoplastic sheet adopts the shape of the mold. A sensor may be placedin the heated sheet before or during the forming process, so that uponcooling, the sheet adopts a desired shape and the sensor is embedded inwhole or part in the thermoplastic sheet.

As another example, the polymer may be fabricated by a molding process,whereby solid or molten polymer or pre-polymer is placed within a mold.Upon cooling, the polymer will adopt the configuration of the mold.Various types of molding process that may be used. For example,compression molding squeezes a pre-polymer into a pre-heated mold andthen applies heat and pressure to the pre-polymer, causing thepre-polymer to cure into the shape of the mold. This process may be usedfor both thermoplastic and thermosetting polymer. In blow molding, aheated hollow thermoplastic tube is inflated within a closed mold untilit adopts the shape of the mold. Upon cooling, the newly shaped tubewill retain the shape of the mold.

Electrospinning is particularly suited for preparing polymeric fibers,and represents another example of fabricating a polymer. For example, itcan be used to form nanofibers from various organic polymers. See, e.g.,Doshi, J. and Reneker, D. H., Journal of Electrostatics 35(2-3):151-160,1995. Fibers formed from electrospinning may be made into variousshapes, including matrices formed from woven and non-woven fibers.Sensors may be embedded within the matrix formed from the electrospunfibers.

As yet another example, the medical article may be formed by any ofweaving, plying, braiding, knitting, and stitching of polymeric fibers.These processes may be used to form various shapes, including a sheet(as found, e.g., in a mesh), filament (as found, e.g., in a suture), anda tube (as found, e.g., in a graft). See, e.g., U.S. Pat. No. 5,378,469directed to high strength collagen threads, which are optionallycrosslinked, where the threads may be used to form braided constructs,plied into yarn, and knitted to provide an implant. A sensor asdescribed herein can be incorporated in, or associated with, thebraided, knitted, or woven materials.

The medical polymer may be sterilized by techniques known in the art.For example, the medical polymer may be exposed to ionizing radiation,such as gamma radiation and electron beam radiation. While ionizingradiation may sterilize the medical polymer, it can also cause somebreakdown of the polymer's basic structure. To combat this problem,stabilizers may be added to the polymer, where examples includeantioxidants such as phenolics that react with free radicals, andorgano-phosphorous compounds which react with peroxide andhydroperoxides generated by the reaction of oxygen with reactive sitesgenerated by the ionizing radiation. Another sterilization technique isto expose the medical polymer to ethyelene oxide. An advantage ofethylene oxide sterilization is that it is not harmful to the structureof the polymer, and accordingly is a suitable sterilization techniquewhen a medical polymer must be repeated sterilized. Anothersterilization technique is to expose the medical polymer to hightemperature, optionally in the presence of steam, e.g., in an autoclave.

B.9.D. Use of Medical Polymers in Medical Polymers and Implants

Polymers containing ISMs can be utilized in a wide variety of medicaldevices and implants, including for example, hip and knee prosthesis,tubes (e.g., grafts and catheters), implants (e.g., breast implants),spinal implants, orthopedic and general surgery implants, andcardiovascular implants (e.g., stents, stent grafts, and heart valves).Representative examples of such implants are discussed in more detail inInternational Patent Application No. PCT/US2013/077356; InternationalPatent Application No. PCT/US2014/028323; International PatentApplication No. PCT/US2014/028381; International Patent Application No.PCT/US2014/043736; U.S. Provisional Patent Application Entitled‘Devices, Systems and Methods for Using and Monitoring Catheters’, filedJun. 25, 2014, Attorney Docket No. CANA.405P1; U.S. Patent ProvisionalApplication Entitled ‘Devices, Systems and Methods for Using andMonitoring Implants, filed Jun. 25, 2014, Attorney Docket No.CANA.406P1; U.S. Patent Provisional Application Entitled ‘Devices,Systems and Methods for Using and Monitoring Spinal Implants’, filedJun. 25, 2014, Attorney Docket No. CANA.407P1; U.S. Patent ProvisionalApplication Entitled ‘Devices, Systems and Methods for Using andMonitoring Orthopedic Hardware’, filed Jun. 25, 2014, Attorney DocketNo. CANA.408P1; U.S. Patent Provisional Application Entitled ‘Devices,Systems and Methods for Monitoring Heart Valves’, filed Jun. 25, 2014,Attorney Docket No. CANA.410P1; all of the aforementioned patentapplications incorporated herein by reference in their entireties forall purposes.

Some additional discussion of medical polymers and devices that can beused in the present invention is as follows:

B 9.D.1. Glues, Adhesives and Cements

The medical polymer may be useful to hold tissue together, or to holdtissue together with a medical implant, such as a glue or adhesive,where the tissue includes soft tissue or bone. When used in bone, themedical polymer is frequently referred to as a bone cement, where bonecement is also used to fill in cavities of bone. For example, thepolymer may be the reaction product of two synthetic polyethyleneglycols which have reactive endgroups such that upon forming a mixtureof the two components, the two materials react with one another and forma crosslinked film. A version of this material is commercially availableas COSEAL (Baxter Healthcare, Fremont, Calif., USA). See, e.g., Cannata,A., et al., Ann. Thorac. Surg. 2013, 95:1818-1826. COSEAL may be spayedover a large area, and to varying depths, to provide a glue or adhesivelayer on living tissue. A modified chitosan-dextran gel as prepared bythe process described in Liu G., et al. Macromolecular Symposia 2009279:151. See, e.g., Lauder, C. I. W., et al. Journal of SurgicalResearch 2012 176:448-454. This material may be applied to soft tissueand will function to hold the tissue together. A sprayable material thatfunctions primarily as a barrier but also has some adhesive propertiesis marketed by Covidien and known as SprayShield. SprayShield is asynthetic two-component product that forms a gel when applied to anorgan.

As an example, a syringe containing a product such as COSEAL can bedelivered along with, or admixed with an ISM as provided herein. Withinvarious embodiments one or more ISMs having sensors (e.g., fluidpressure sensors, contact sensors, position sensors, pulse pressuresensors, liquid (e.g., blood) volume sensors, liquid (e.g., blood) flowsensors, chemistry sensors (e.g., for blood and/or other fluids),metabolic sensors (e.g., for blood and/or other fluids), accelerometers,mechanical stress sensors and temperature sensors) can be incorporatedinto one or more polymers.

B.9.D.2. Medical Polymers—Meshes and Films

Various medical polymers are used to form implantable films of meshes.For example, the biodegradable copolymer of hydroxybutyrate andhydroxyvalerate known as (PHBV) is available from Metabolix, Inc.(Cambridge, N.J., USA) and can function as a barrier film. Oxidizedregenerated cellulose is commercially available as Interceed (Johnson &Johnson, Canada), which is a knitted fabric that converts to a gelwithin 8 hours and is completely cleared from the body within 28 days.See, e.g., Larsson B., J. Reprod. Med. 1996, 41:27-34 and ten Broek R.P. G., et al., The Lancet 2014 383:48-59. Collagen foil in combinationwith polypropylene mesh is commercially available as TissueFoil E fromBaxter (Germany). See, e.g., Schonleben, F., Int. J. Colorectal Dis.2006, 21(8):840-6. INTERCOAT, also known as OXIPLEX AP, made by Johnson& Johnson and licensed from Fziomed, may be used as an implantable film.PREVADH, made by Sofradim-Covidien in France is a collagen film andfleece composite that may be used as an implantable filem. W.L. Goremanufactures and sells non-absorbable adhesion barrier films usingexpanded polytetrafluoroethylene film, sometimes referred to as GoreTexSurgical Membrane or as Preclude. Each of these films may be used as amedical polymer according to the present invention.

Meshes are available from various vendors. For example, Ethicon marketsa synthetic mesh, PROLENE mesh, made from polypropylene. Biologicalmeshes are also known and may be used in the present invention. Examplesare meshes formed from human or animal dermis or porcine smallintestinal submucosa. See, e.g., Nguyen et al., JAMA Surg., epub Feb.19, 2014 and Carbonell et al., J. Am. Coll. Surg., 217(6):991-998, 2013.

Within one embodiment of the invention one or more ISMs can beincorporated into a mesh (e.g., by interweaving, attaching,interlayering, or otherwise securing the ISM to the mesh).Representative examples of ISMs have one or more sensors such as fluidpressure sensors, contact sensors, position sensors, pulse pressuresensors, liquid (e.g., blood) volume sensors, liquid (e.g., blood) flowsensors, chemistry sensors (e.g., for blood and/or other fluids),metabolic sensors (e.g., for blood and/or other fluids), accelerometers,mechanical stress sensors and temperature sensors. Sensors within a meshor film can be utilized to determine contact between various organs oranatomical structures (e.g. utilizing contact sensors and/or pressuresensors); the presence of or development of an infection (e.g.,utilizing temperature and/or metabolic sensors), to determinedegradation, wear, movement and/or fracture (e.g., utilizing contactsensors, pressure sensors, and/or location sensors).

B.9.D.3. Medical Polymers—Suture and Staples

The medical polymer may be formed into a device for securing orfastening tissue, such as a staple or a suture. See, e.g., U.S. Pat.Nos. 8,506,591 and 8,721,681 as well as U.S. Publication Nos.2001/0027322, 2006/0253131, 2011/0093010, 2013/0165971, and 2014/0130326for exemplary suitable staples and discussion of insertion devices. Themedical polymer may be formed into a suture, e.g., PROLENE polypropylenesuture by Ethicon (New Jersey), or DEKLENE polypropylene suture sold byTeleflex Medical (North Carolina). See also, e.g., U.S. Pat. Nos.6,908,466; 4,750,492; 4,662,068 for medical fasteners prepared in wholeor part from polymer.

Within one embodiment of the invention one or more ISMs can beincorporated into, or otherwise attached or secured to a fixation devicesuch as a suture or staple. The Isms can have one or more sensors suchas fluid pressure sensors, contact sensors, position sensors, pulsepressure sensors, liquid (e.g., blood) volume sensors, liquid (e.g.,blood) flow sensors, chemistry sensors (e.g., for blood and/or otherfluids), metabolic sensors (e.g., for blood and/or other fluids),accelerometers, mechanical stress sensors and temperature sensors.Sensors within a suture or staple can be utilized to determine contactwith various organs or anatomical structures (e.g. utilizing contactsensors and/or pressure sensors); the presence of or development of aninfection (e.g., utilizing temperature and/or metabolic sensors), todetermine degradation, wear, movement and/or fracture (e.g., utilizingcontact sensors, pressure sensors, and/or location sensors).

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of polymersfor use with ISMs are provided in U.S. Provisional No. 62/017159, whichis hereby incorporated by reference in its entirety).

B.10. Heart Valves

Within another aspect of the invention, ISMs as described herein areprovided for use in one or more types of heart valves. As utilizedherein “heart valve” refers to a device which can be implanted into theheart of a patient with valvular disease. There are three principletypes of heart valves: mechanical, biological, and tissue-engineered(although, for purposes of this disclosure tissue-engineered valves willbe considered along with other biological valves). Mechanical andbiological valves typically fall into two categories: 1) heart valvesfor surgical procedures utilizing a sternotomy or “open heart” procedure(e.g., ‘caged ball’, ‘tilting disc’, bileaflet and trileaflet biologicdesigns with sewing rings for attachment in the valvular annulus); and2) heart valves which are percutaneously implanted [e.g., either a stentframed (self-expanding stent or balloon-expandable stent) or non-stentframed design] that can often contain valve cusps which are fabricatedfrom biological sources (bovine or porcine pericardium). Tissue-based or‘biological’ valves are typically made from either porcine or bovinesources, and are usually prepared either from the valve of the animal(e.g., a porcine valve), or from tissue of the pericardial sac (e.g., abovine pericardial valve or a porcine pericardial valve).Tissue-engineered valves are valves that have been artificially createdon a scaffold (e.g., through the growth of suitable cells on a tissuescaffold). Tissue-engineered valves have not yet been commerciallyadopted.

In addition to heart valves, delivery devices are also provided. In thecontext of percutaneous heart valve delivery, particularly preferreddelivery devices comprise a guidewire, delivery catheter, catheters witha “sheath” that deploy self-expanding devices, catheters with anexpandable balloon, and anchoring suture devices. By utilizing suchdevices and methods heart valves can be replaced without the need foropen heart surgery.

Representative examples of heart valves and associated delivery devicesare described in U.S. Pat. Nos. 6,564,805, 6,730,122, 7,033,090,7,578,842, 8,142,497, 8,287,591, and 8,568,474; U.S. Publication Nos.2010/0076548, 2010/0161046, 2010/117471, 2011/0009818, 2011/0190897,2012/0179243, 2013/0096671, 2013/0166023, 2013/0268066; and PCTPublication Nos. WO 2012/011108, and WO 2013/021374; all of the above ofwhich are incorporated by reference in their entirety.

The present invention provides heart valves and related deliverydevices, all of which have sensors as described in further detail below.The heart valve and related delivery devices are preferably sterile,non-pyrogenic, and/or suitable for use and/or implantation into humans.However, within certain embodiments of the invention the heart valveand/or delivery device can be made in a non-sterilized environment (oreven customized or “printed” for an individual subject), and sterilizedat a later point in time.

B.10.A. Heart Valves and their Use

B.10.A.1. Mechanical Heart Valves and their Use

B.10.A.1.1. ‘Open Heart’ Surgery Heart Valves: “Caged Ball”, “TiltingDisc”, and Bi and Tri-Leaflet Designs

As noted above, within various embodiments of the invention, mechanicalheart valves are provided with one or more ISMs as described herein.Representative examples include: 1) heart valves based upon a “cagedball” design [e.g., these devices have a restraining cage (typicallymade of metal), an occluder ball (typically made from a siliconeelastomer), and a suture ring) such as the Starr-Edwards valve and theSmeloff-Cutter valve]; 2) heart valves based upon a “tilting disc”design [typically including an occluder disc that rotates on a flangeand 2 metal struts (an inlet and an outlet strut) which stop theoccluder disc in either the open or the closed position; additionally,there is a metal ring covered by ePTFE that is used as a suture ring toanchor the valve in place]; and 3) bileaflet and trileaflet valves (withtwo or three hinged leaflets and a anchoring suture ring).

Mechanical valves have improved greatly since their introduction, yetthey still suffer from numerous complications. For example, thecaged-ball design can last for a long time, but require a lifetime ofanticoagulation for the patient. Red blood cells and platelets getdamaged flowing through the mechanical valves which can lead to ahypercoagulative state that can result in thrombus and embolis formation(necessitating blood thinner therapy) and can even result in anemia. Theleaflet (bileaflet and trileaflet) mechanical valves cause less damageto blood cells (and are less thrombogenic and require lower levels ofanticoagulation therapy), but they are vulnerable to backflow.Mechanical valves are also subject to impact wear (occurs in the hingesof bileaflet valves, between the occluder and ring in tilting discvalves, and between the ball and cage in ball-cage valves) andfrictional wear (occurs between the occluder and the struts in tiltingdisc valves and between the leaflet pivots and hinge cavities inbileaflet valves), and can cause ‘cavitation’ (i.e., the formation ofmicrobubbles, which can erode the valve surface, increase blood celldamage and increase the incidence of thromboembolic events).

Hence, the present invention provides mechanical heart valves which haveone or more ISMs having one or more sensors, including for example,fluid pressure sensors, contact sensors, accelerometers, vibrationsensors, pulse sensors, liquid (e.g., blood) volume sensors, liquid(e.g., blood) flow sensors, liquid (e.g., blood) chemistry sensors,liquid (e.g., blood) metabolic sensors, mechanical stress sensors, andtemperature sensors. Such sensors can be placed on, in, or within thevarious components of the heart valve, and can be utilized to monitor,amongst other things, thrombogenesis, wear, blockage, sticking (impairedmovement of the ‘valve’), trans-valvular pressure gradients (anindicator of the potential for cavitation), cardiac function, leakage(backflow or regurgitation), detachment of the suture ring (from, forexample, suture breakage), assembly of the device (where possible),correct anatomical placement of the device, failure, and safety. Withinpreferred embodiments of the invention ISMs can be provided on thesewing ring or other sites that are utilized to attach the valve to theheart.

For example, as shown in FIGS. 31A and 31B, mechanical valves areillustrated with an ISM incorporated. Within one embodiment, an ISMcontaining blood flow (motion) sensors are provided on a mechanicalheart valve (e.g., ‘caged-ball’, ‘tilting disc’, bi or tri-leafletvalves).

ISMs having blood flow sensors can be utilized to measure fluid flowthrough the mechanical valve, and to detect abnormalities that occuracutely, or gradually over time. The ISMs can be provided in a varietyof locations, but are preferred within the suture ring (‘10’ as shown inFIGS. 31A and 31B); other preferred location include incorporation intothe leaflets, the occluder disc/ring, the cage/ball, and the struts. Forexample, a decrease in forward flow may suggest the development of astenosis [from thrombus formation, infection (biofilm or vegetations)],sticking of moving components (the ball, disc, or leaflets), or failureof the device. Increases in backwards flow can be suggestive ofregurgitation, due to sticking, thrombus, infection or failure of themoving components. ISM blood flow sensors can show real-time movement ofblood through the valve, and permit hemodynamic monitoring anddetermination of cardiac output (similar to an echocardiogram), ejectionfraction and cardiac index (key clinical measurements that are valuablein monitoring cardiac-compromised patients, which many valvular patientsare).

Within other embodiments, ISMs are provided having one or more pressuresensors which can be utilized to measure pressure on both sides of thevalve, and to detect abnormalities that occur acutely, or gradually overtime. The ISMs containing pressure sensors can be provided in a varietyof locations (particularly such that sensors are located on both theatrial and ventricular side of the valve), but are preferred within thesuture ring (‘10’ as shown in FIGS. 31A and 31B); other preferredlocation include incorporation into the leaflets, the occluderdisc/ring, the cage/ball, and the struts. For example, an increasedpressure gradient across the valve can indicate occlusion due tothrombus, panus, or in the case of biologic valves restrictive leafletimmobility due to calcification. Excessive regurgitation can be anindication of the prosthetic valve leaflet's inability to seat on thehousing (mechanical valves) or coapt (biological valves) properly due tothrombus, panus, and/or calcification. Valvular regurgitation can alsooccur due to perivalvular leakage at the interface of the valve's suturering with the host annulus. ISM pressure sensors on the ventricular sideof a valve can measure systolic and diastolic pressure, and estimatesystemic vascular resistance and pulmonary vascular resistance(depending upon the valve). These sensor readings can also be utilizedto calculate cardiac output, ejection fraction and cardiac index andpermit in situ hemodynamic monitoring.

Within further embodiments ISMs are provided having one or more bloodvolume sensors which can be utilized to measure fluid flow through thevalve, and to detect abnormalities that occur acutely, or gradually overtime. The ISMs containing blood volume sensors can be provided in avariety of locations (particularly such that sensors are located on boththe atrial and ventricular side of the valve), but are preferred withinthe suture ring (‘10’ as shown in FIGS. 31A and 31B); other preferredlocation include incorporation into the leaflets, the occluderdisc/ring, the cage/ball, and the struts. For example, a decrease inforward blood volume may suggest the development of a stenosis [fromthrombus formation, infection (biofilm or vegetations)], sticking ofmoving components (the ball, disc, or leaflets), or failure of thedevice. Increases in backwards blood volume (>5 ml) can be suggestive ofregurgitation, due to sticking, thrombus, infection or failure of themoving components. ISM blood volume sensors (e.g., to measure bloodvolume over a unit of time) can show real-time movement of blood throughthe valve, and permit hemodynamic monitoring and determination ofcardiac output (similar to an echocardiogram), ejection fraction andcardiac index and permit in situ hemodynamic monitoring.

Within yet other embodiments ISMs are provided having metabolic (orchemical) sensors on mechanical valves which can be utilized to measuremetabolic parameters important in vascular function. The ISMs containingmetabolic can be provided in a variety of locations, but are preferredwithin the suture ring (‘10’ as shown in FIGS. 31A and 31B); otherpreferred location include incorporation into the leaflets, the occluderdisc/ring, the cage/ball, and the struts; they must be blood contacting.Representative examples include coagulation/clotting parameters such asPT, PTT, clotting time and INR; Blood Oxygen content; Blood CO₂ content;Blood pH; Blood cholesterol; Blood lipids (HDL, LDL); Blood Glucose;Cardiac enzymes; Hepatic Enzymes; Electrolytes; Blood Cell Counts; andKidney Function parameters (BUN, Creatinine, etc.).

Within other embodiments, ISMs are provided with position sensors thatcan be utilized to measure the location of fixed and moving componentsof the mechanical valve. The ISMs can be provided in a variety oflocations, but are preferred within the suture ring (‘10’ as shown inFIGS. 31A and 31B); other preferred location include incorporation intothe leaflets, the occluder disc/ring, the cage/ball, and the struts. Forexample, gaps in the leaflets, occluder disc/ring and cage/ball aresuggestive of leakage and regurgitation. ISM position sensors can alsobe utilized to ‘image’ valvular motion (opening, closing, and integrityof the seal). Changes in ISM position sensors on the suture ring canshow slippage, migration, failure, and suture breakage. Dilation of thering can indicate possible dilative cardiomyopathy, whereas narrowing ofthe ring can indicate myocardial hypertrophy.

Within further embodiments ISMs are provided with contact sensors thatcan be utilized to measure the contact between fixed and movingcomponents of a mechanical valve. For example, incomplete contactbetween the leaflets, between the occluder disc and the ring, andbetween the ball and cage are suggestive of leakage and regurgitation.The ISMs containing contact sensors can be provided in a variety oflocations, but are preferred within the suture ring (‘10’ as shown inFIGS. 31A and 31B); other preferred locations include incorporation intothe leaflets, the occluder disc/ring, the cage/ball, and the struts.Contact sensors can also be utilized to ‘image’ valvular motion(opening, closing, and integrity of the seal). Changes in contactsensors on the suture ring can show slippage, migration, failure, andsuture breakage. ISM contact sensors can also be utilized to monitor thesurface of the valve (e.g., to detect the presence of surface anomaliessuch as the formation of clot or thombi, biofilm or vegetations on thevalve surface), and to monitor for friction wear, impact wear, andbreakage (e.g., contact sensors can be placed at various depths of anyof the various components (e.g., occluder disc, strut, occluder ring,leaflets, leaflet pivots, hinges, ball and/or cage).

Within yet other embodiments ISMs are provided with accelerometers whichcan be utilized to measure the location and movement of fixed and movingcomponents of a mechanical valve. The ISMs containing accelerometers canbe provided in a variety of locations, but are preferred within thesuture ring (‘10’ as shown in FIGS. 31A and 31B); other preferredlocations include incorporation into the leaflets, the occluderdisc/ring, the cage/ball, and the struts. For example, gaps in theleaflets, occluder disc and ring, and ball and cage are suggestive ofleakage and regurgitation. Accelerometers can also be utilized to‘image’ real time valvular motion (opening, closing, and integrity ofthe seal), and to image changes that might occur in the mechanical valveover time. Changes in accelerometers on the suture ring can showslippage, migration, failure, and suture breakage.

B.10.A.1.2. Biological (Tissue-Based) Heart Valves and their Use

As noted above, within various embodiments of the invention biological(tissue-based) heart valves are provided with one or more ISMs asdescribed herein. Briefly, biological valves are heart valves that aretypically designed from xenographic (i.e., from a different species)tissue. Most typically, biological heart valves are constructed fromporcine or bovine (usually either valvular or pericardial) tissue,although other animal tissues (e.g., equine) have also been utilized.

For purposes of this disclosure, tissue-engineered valves can also beconsidered to be a biological valve. Briefly, tissue-engineered valvesgenerally comprise a layer of cells (e.g., fibroblasts, stem cells, orsome combination of cells), that are grown over a tissue scaffold(typically a synthetic polymer-based scaffold, see generally Lichtenberget al., ‘Biological scaffolds for heart valve tissue engineering”,Methods Mol. Med. 2007; 140:309-17; see also U.S. Pub. No. 2010/117471).

Biological valves have a number of advantages in that they do not damagered blood cells or platelets (and therefore do not requireanticoagulation therapy) after the healing of the suture ring and theydo not cause cavitation like mechanical valves. However, they stillsuffer from several complications, including for example: 1) they have amore limited lifespan than mechanical valves; 2) they can cause animmune reaction; 3) they can clot and form emboli (causing strokes ormyocardial infarction); 4) they can also become infected and form septicemboli; 5) they can become covered with fibrous tissue; and 6) they canbecome calcified. Common biological valves are currently made by EdwardsLifesciences, Medtronic, St. Jude, Sorin, 3F Therapeutics, CryoLife andLifeNet Health.

Hence, the present invention provides biological heart valves which haveone or more ISMs having one or more sensors, including for example,fluid pressure sensors, contact sensors, accelerometers, vibrationsensors, pulse sensors, liquid (e.g., blood) volume sensors, liquid(e.g., blood) flow sensors, liquid (e.g., blood) chemistry sensors,liquid (e.g., blood) metabolic sensors, biological stress sensors, andtemperature sensors. Such ISMs can be placed on, in, or within thevarious components of the heart valve, and can be utilized to monitor,amongst other things, thrombogenesis, infection (vegetations), wear,blockage, sticking (impaired movement of the valve leaflets),trans-valvular pressure gradients, leakage (backflow or regurgitation),detachment of the suture ring (from, for example, suture breakage),correct anatomical placement of the device, failure, and safety.

FIGS. 32A and 32B schematically illustrate biological valves withrepresentative ISMs. Within one embodiment ISMs are provided with bloodflow (motion) sensors on a biological heart valve. The ISMs containingblood flow sensors can be provided in a variety of locations(particularly such that sensors are located on both the atrial andventricular side of the valve), but are preferred within the suture ring(‘10’ as shown in FIG. 32A) and the leaflet supports (‘10” in FIG. 32B);another preferred location includes incorporation into the leaflets (forpericardial valves). ISM blood flow sensors can be utilized to measurefluid flow through the valve, and to detect abnormalities that occuracutely, or gradually over time. For example, a decrease in forward flowmay suggest the development of a stenosis [from thrombus formation,infection (biofilm or vegetations), fibrosis, or calcification],sticking of the leaflets, or failure of the device. Increases inbackwards flow can be suggestive of regurgitation, due to sticking,thrombus, infection, fibrosis, calcification or failure of the movingcomponents. ISM blood flow sensors can show real-time movement of bloodthrough the valve, and permit hemodynamic monitoring and determinationof cardiac output (similar to an echocardiogram), ejection fraction andcardiac index (key clinical measurements that are valuable in monitoringcardiac-compromised patients, which many valvular patients are).

Within other embodiments, ISMs are provided with pressure sensors whichcan measure pressure on both sides of the valve, and to detectabnormalities that occur acutely, or gradually over time. The ISMscontaining pressure sensors can be provided in a variety of locations(particularly such that sensors are located on both the atrial andventricular side of the valve), but are preferred within the suture ring(‘10’ as shown in FIG. 32A) and the leaflet supports (‘10” in FIG. 32B);another preferred location includes incorporation into the leaflets (forpericardial valves). Excessive regurgitation can be an indication of theprosthetic valve leaflet's inability to coapt properly due to thrombus,panus, and/or calcification. Valvular regurgitation can also occur dueto perivalvular leakage at the interface of the valve's suture ring withthe host annulus. ISM pressure sensors on the ventricular side of abiological valve can measure systolic and diastolic pressure, andestimate systemic vascular resistance and pulmonary vascular resistance(depending upon the valve). These sensor readings can also be utilizedto calculate cardiac output, ejection fraction and cardiac index andpermit in situ hemodynamic monitoring.

Within further embodiments ISMs are provided with blood volume sensorswhich can be utilized to measure fluid volume through the valve, and todetect abnormalities that occur acutely, or gradually over time. TheISMs containing blood volume sensors can be provided in a variety oflocations (particularly such that sensors are located on both the atrialand ventricular side of the valve), but are preferred within the suturering (‘10’ as shown in FIG. 32A) and the leaflet supports (‘10” in FIG.32B); another preferred location includes incorporation into theleaflets (for pericardial valves). For example, a decrease in forwardblood volume may suggest the development of a stenosis [from thrombusformation, infection (biofilm or vegetations), fibrosis, calcification],sticking of the leaflets, or failure of the device. Increases inbackwards blood volume (>5 ml) can be suggestive of regurgitation, dueto sticking, thrombus, infection, fibrosis, calcification, or failure ofthe moving components. ISM blood volume sensors (e.g., to measure bloodvolume over a unit of time) can show real-time movement of blood throughthe valve, and permit hemodynamic monitoring and determination ofcardiac output (similar to an echocardiogram), ejection fraction andcardiac index and permit in situ hemodynamic monitoring.

Within yet other embodiments ISMs are provided with metabolic (orchemical) sensors can be utilized to measure metabolic parametersimportant in vascular function. Representative examples include:Coagulation/Clotting parameters such as PT, PTT, clotting time and INR;Blood Oxygen content; Blood CO₂ content; Blood pH; Blood cholesterol;Blood lipids (HDL, LDL); Blood Glucose; Cardiac enzymes; HepaticEnzymes; Electrolytes; Blood Cell Counts; and Kidney Function parameters(BUN, Creatinine, etc.).

Within other embodiments ISMs are provided with position sensors thatcan be utilized to measure location of fixed and moving components of abiological valve. The ISMs containing position sensors can be providedin a variety of locations (particularly such that sensors are located onboth the atrial and ventricular side of the valve), but are preferredwithin the suture ring (‘10’ as shown in FIG. 32A) and the leafletsupports (‘10” in FIG. 32B); another preferred location includesincorporation into the leaflets (for pericardial valves). For example,gaps in the leaflets (upon closing of the valve) are suggestive ofleakage and regurgitation. ISM position sensors can also be utilized to‘image’ valvular motion (opening, closing, and integrity of the seal).Changes in position sensors on the suture ring can show slippage,migration, failure, and suture breakage. Dilation of the ring canindicate possible cardiomyopathy, whereas narrowing of the ring canindicate myocardial hypertrophy.

Within further embodiments ISMs are provided with contact sensors thatcan be utilized to measure location of fixed and moving components. TheISMs containing contact sensors can be provided in a variety oflocations (particularly such that sensors are located on both the atrialand ventricular side of the valve), but are preferred within the suturering (‘10’ as shown in FIG. 32A) and the leaflet supports (‘10” in FIG.32B); another preferred location includes incorporation into theleaflets (for pericardial valves). For example, gaps in the leaflets(upon closing of the valve) are suggestive of leakage and regurgitation.ISM contact sensors can also be utilized to ‘image’ valvular motion(opening, closing, and integrity of the valvular seal). Changes incontact sensors on the suture ring can show slippage, migration,failure, and suture breakage. ISM contact sensors can also be utilizedto monitor the surface of the valve (e.g., to detect the presence ofsurface anomalies such as the formation of clot or thombi, biofilm orvegetations, fibrosis or calcification on the valve surface), and tomonitor for friction wear, impact wear, tears and breakage of theleaflets.

Within yet other embodiments ISMs are provided with accelerometers whichcan be utilized to measure the location and movement of fixed and movingcomponents of a biological valve. The ISMs containing accelerometers canbe provided in a variety of locations (particularly such that sensorsare located on both the atrial and ventricular side of the valve), butare preferred within the suture ring (‘10’ as shown in FIG. 32A) and theleaflet supports (‘10” in FIG. 32B); another preferred location includesincorporation into the leaflets (for pericardial valves). For example,gaps in the leaflets during valve closure are suggestive of leakage andregurgitation and integrity of the seal), and to image changes thatmight occur over time. Changes in accelerometers on the suture ring canshow slippage, migration, failure, and suture breakage.

Within yet other embodiments of the invention any of the ISMs describedherein can be placed in mitral or tri-cuspid annuloplasty rings (e.g.,2-D Carpentier Edwards rings and 3-D MDT Colvin-Gallaway or Duranrings).

B.10.A.1.3. Percutaneous Heart Valves and their Use

Within other aspects of the invention percutaneous heart valves (andtheir associated delivery devices) are provided with a variety ofsensors described herein. Briefly, percutaneous aortic valve replacement(PAVR) or transcatheter aortic valve replacement (TAVR) is thereplacement of the aortic valve through blood vessels or other minimallyinvasive techniques (thus eliminating a need for ‘open-heart’ surgery).Typically, the heart is accessed through the femoral artery in the leg,apically (through the apex of the heart), through the subclavianarteries, or via the aorta. Two companies have currently approveddevices for aortic valve replacement: 1) COREVALVE (Medtronic); and 2)SAPIEN (Edwards Lifesciences). Other percutaneous aortic valves,percutaneous mitral valves and other percutaneous heart valves are underdevelopment.

The COREVALVE (Medtronic) is schematically illustrated in FIGS. 33A and33B. Briefly, it is composed of a self-expanding nitinol support frame(stent) with cells in a diamond design (see FIG. 33A). It is fitted withbovine or procine pericardium shaped into valve leaflets, and providedalong with a 18F delivery catheter. The SAPIEN (Edwards Lifesciences) isa trileaflet heart valve constructed of bovine pericardium which ismounted on a balloon-expandable stainless steel stent (see FIGS. 34A and34B).

Percutaneous heart valve delivery has a number distinct advantages,including the fact that they do not require open heart surgery forplacement, and hence can be utilized in high-risk patients that mightnot live through such a surgery. However, they still suffer fromcomplications, including for example: 1) cardiogenic shock, strokeand/or death; 2) perforation of the myocardium; 3) cardiac tamponade; 4)ascending aorta trauma; 5) embolism; 6) thrombosis; 7) valve migration;8) valve regurgitation; and 9) a variety of other valve dysfunctions[e.g., breaking or fracturing of the valve frame, incomplete expansion,bending, build-up of minerals (calcification) or clots (thrombosis),wear and tear, pannus (fibrous tissue) formation that might block thevalve, and failures during the surgical procedure (e.g., failure toproperly size and/or place the valve)].

Hence, the present invention provides percutaneous heart valves and/ortheir associated delivery devices (guidewires, catheters, ballooncatheters, anchoring devices) which have one or more ISMs having one ormore sensors, including for example, fluid pressure sensors, contactsensors, position sensors, accelerometers, vibration sensors, pulsesensors, liquid (e.g., blood) volume sensors, liquid (e.g., blood) flowsensors, liquid (e.g., blood) chemistry sensors, liquid (e.g., blood)metabolic sensors, stress sensors, and temperature sensors. Such sensorscan be place on, in, or within the various components of the heartvalve, and can be utilized to monitor, amongst other things, properplacement of the valve, anatomical location of the valve, pressureexerted on surrounding tissues, balloon inflation/deflation, stentscaffold expansion, deployment of the valve, migration, thrombogenesis,infection (vegetations), calcification, fibrous tissue accumulation,wear, blockage, sticking (impaired movement of the ‘valve’),trans-valvular pressure gradients, leakage (backflow or regurgitation),detachment, leaflet damage, assembly of the device (where possible),failure, and safety.

FIGS. 33A, 33B, 34A and 34B schematically illustrate percutaneous valvesand their associated delivery devices (guidewires, catheters, ballooncatheters, anchoring devices) with a variety of ISM sensors. Within oneembodiment ISMs are provided with one or more blood flow (motion)sensors are provided on a percutaneous heart valve and/or deliverydevice. The ISMs containing blood flow sensors can be provided in avariety of locations on the percutaneous valve (particularly such thatsensors are located on both the atrial and ventricular side of thevalve), but are preferred within the stent support, stent covering,anchoring ring and leaflet supports. ISMs with blood flow sensors canalso be provided on a variety of locations on the delivery devices suchas on/in the guidewires, catheters, balloon catheters, anchoringdevices. ISM blood flow sensors can be utilized to measure fluid flowthrough the valve and/or delivery device, and to detect abnormalitiesthat occur acutely, or gradually over time. During percuatenousplacement of the valve, ISM blood flow sensors on the valve and/ordelivery devices can be used to ensure that adequate blood circulationis being maintained and that the device assembly is not criticallyobstructing cardiac outflow and output. After deployment, changes inflow through the implanted valve can provide valuable clinicalinformation. For example, a decrease in forward flow through the valveleaflets may suggest the development of a stenosis [from thrombusformation, infection (biofilm or vegetations), fibrosis, orcalcification], sticking of the leaflets, or failure of the device.Increases in backwards flow can be suggestive of regurgitation, due tosticking, thrombus, infection, fibrosis, calcification or failure of themoving components. Blood flow sensors can also detect leakage through oraround the valve frame. ISM blood flow sensors can show real-timemovement of blood through the valve, and permit hemodynamic monitoringand determination of cardiac output (similar to an echocardiogram),ejection fraction and cardiac index (key clinical measurements that arevaluable in monitoring cardiac-compromised patients, which many valvularpatients are).

Within other embodiments, ISMs are provided with one or more pressuresensors which can be utilized to measure pressure on both sides of thevalve and/or delivery device, and to detect abnormalities that occuracutely, or gradually over time. The ISMs containing pressure sensorscan be provided in a variety of locations on the percutaneous valve(particularly such that sensors are located on both the atrial andventricular side of the valve), but are preferred within the stentsupport, stent covering, anchoring ring and leaflet supports. ISMs withpressure sensors can also be provided on a variety of locations on thedelivery devices such as on/in the guidewires, catheters, ballooncatheters, anchoring devices. During percuatenous placement of thevalve, ISM pressure sensors on the valve (particularly the metallicstent scaffold) and/or delivery devices (particularly the deliveryballoon) can be used to monitor the pressure being applied tosurrounding tissues. This can help prevent procedural complications suchas damage to the wall of the aorta or myocardium and/or perforation ofthese tissues. After deployment, changes in pressures across theimplanted valve can provide valuable clinical information. For example,an increased pressure gradient across the valve can indicate stenosis. Alow, or decreasing, pressure gradient can indicate regurgitation and/orpossible valve failure. ISM pressure sensors on the ventricular andaortic side of a percutaneous valve can measure systolic and diastolicpressure, and estimate systemic vascular resistance. These sensorreadings can also be utilized to calculate cardiac output, ejectionfraction and cardiac index and permit in situ hemodynamic monitoring.

Within further embodiments ISMs are provided with blood volume sensorswhich can be utilized to measure fluid flow through the percutaneousvalve and/or associated delivery devices, and to detect abnormalitiesthat occur acutely, or gradually over time. The ISMs containing bloodvolume sensors can be provided in a variety of locations on thepercutaneous valve (particularly such that sensors are located on boththe atrial and ventricular side of the valve), but are preferred withinthe stent support, stent covering, anchoring ring and leaflet supports.ISMs with blood volume sensors can also be provided on a variety oflocations on the delivery devices such as on/in the guidewires,catheters, balloon catheters, anchoring devices. During percuatenousplacement of the valve, ISM blood volume sensors on the valve and/ordelivery devices can be used to ensure that adequate systemic bloodvolume is being maintained and that the device assembly is notcritically obstructing cardiac outflow and output. After deployment,changes in blood volume through the implanted valve can provide valuableclinical information. For example, a decrease in forward blood volumemay suggest the development of a stenosis [from thrombus formation,infection (biofilm or vegetations), fibrosis, calcification], stickingof the leaflets, or failure of the device. Increases in backwards bloodvolume (>5 ml) can be suggestive of regurgitation, due to sticking,thrombus, infection, fibrosis, calcification, or failure of the movingcomponents. ISM blood volume sensors (e.g., to measure blood volume overa unit of time) can show real-time movement of blood through the valve,and permit hemodynamic monitoring and determination of cardiac output(similar to an echocardiogram), ejection fraction and cardiac index andpermit in situ hemodynamic monitoring.

Within yet other embodiments ISMs are provided with metabolic (orchemical) sensors which can be utilized on the valve and/or deliverydevices to measure metabolic parameters important in vascular function.Representative examples include Coagulation/Clotting parameters such asPT, PTT, clotting time and INR; Blood Oxygen content; Blood CO₂ content;Blood pH; Blood cholesterol; Blood lipids (HDL, LDL); Blood Glucose;Cardiac enzymes; Hepatic Enzymes; Electrolytes; Blood Cell Counts; andKidney Function parameters (BUN, Creatinine, etc.).

Within other embodiments ISMs are provided with position sensors thatcan be utilized on the percutaneous valve and/or associated deliverydevices to measure the location of fixed and moving components. The ISMswith position sensors can be provided in a variety of locations on thepercutaneous valve (particularly such that sensors are located on boththe atrial and ventricular side of the valve), but are preferred withinthe stent support, stent covering, anchoring ring and leaflet supports.ISMs containing position sensors can also be provided on a variety oflocations on the delivery devices such as on/in the guidewires,catheters, balloon catheters, anchoring devices. During percuatenousplacement of the valve, ISM position sensors on the valve and/ordelivery devices are invaluable in assisting in correct anatomicalplacement of the artificial valve across the native valve. Monitoringposition changes of the device in “real time” during deployment can helpthe clinician place and secure the device correctly. After deployment,changes in position of the implanted valve can indicate migration of thedevice away (upstream or downstream) from its original placement site.ISM position sensors can also be utilized to monitor valve functionafter implantation. For example, gaps in the leaflets upon closing ofthe valve are suggestive of leakage and regurgitation. ISM positionsensors can also be utilized to ‘image’ valvular leaflet motion(opening, closing, and integrity of the seal). Changes in ISM positionsensors located on the stent scaffold can show slippage, migration,failure, and anchoring suture breakage. Dilation of the scaffold canindicate possible overexpansion, breakage or failure; whereas narrowingof the scaffold can indicate possible underexpansion, collapse,breakage, or failure.

Within further embodiments ISMs are provided with contact sensors thatcan be utilized on the percutaneous valve and/or associated deliverydevices to measure the contact between the device and the surroundingtissues, the contact between related device components/moving pieces,and the status of blood-contacting surface of the device. The ISMscontaining contact sensors can be provided in a variety of locations onthe percutaneous valve (particularly such that sensors are located onboth the atrial and ventricular side of the valve), but are preferredwithin the stent support, stent covering, anchoring ring and leafletsupports. ISMs with contact sensors can also be provided on a variety oflocations on the delivery devices such as on/in the guidewires,catheters, balloon catheters, anchoring devices. During percuatenousplacement of the valve, ISM contact sensors on the valve and/or deliverydevices are invaluable in assisting in correct anatomical placement ofthe artificial valve across the native valve. Monitoring contact changesof the device in “real time” during deployment can help the clinicianplace, size, and secure the device correctly. In addition, ISM contactsensors on the valve (particularly the metallic stent scaffold) and/ordelivery devices (particularly the delivery balloon) can be used tomonitor the amount and extent of contact with surrounding tissues. Thiscan help prevent procedural complications such as damage to the wall ofthe aorta or myocardium (and/or perforation of these tissues), monitorfor correct inflation and full deflation of the balloon catheter (ifpresent), and full deployment of the stent scaffold across the nativevalve. After deployment, changes in contact between the implanted valveand surrounding tissues can indicate migration of the device away(upstream or downstream) from its original placement site. ISM contactsensors can also be utilized to monitor valve function afterimplantation. For example, gaps in the valve leaflets (upon closing) aresuggestive of leakage and regurgitation. ISM contact sensors can also beutilized to ‘image’ valvular motion (opening, closing, and integrity ofthe seal) in real time. Increased contact between the stent scaffold andthe vascular wall can indicate possible overexpansion, breakage orfailure; whereas decreased contact between the stent scaffold and thevascular wall can indicate possible under-expansion, collapse, breakage,or failure. ISM contact sensors can also be utilized to monitor theblood-contacting surface of the valve (e.g., to detect the presence ofsurface anomalies such as the formation of clot or thombi, biofilm orvegetations, fibrosis or calcification on the valve surface), and tomonitor for friction wear, impact wear, tears and breakage of theleaflets.

Within yet other embodiments ISMs are provided with accelerometers whichcan be utilized to measure the location and movement of fixed and movingcomponents on the valve and/or delivery devices. The ISMs containingaccelerometers can be provided in a variety of locations on thepercutaneous valve (particularly such that sensors are located on boththe atrial and ventricular side of the valve), but are preferred withinthe stent support, stent covering, anchoring ring and leaflet supports.ISMs with accelerometers can also be provided on a variety of locationson the delivery devices such as on/in the guidewires, catheters, ballooncatheters, anchoring devices. During percuatenous placement of thevalve, accelerometers on the valve and/or delivery devices areinvaluable in assisting in correct anatomical placement of theartificial valve across the native valve. Monitoring movement of thedevice in “real time” during deployment can help the clinician place,size, and secure the device correctly. In addition, accelerometers onthe valve (particularly the metallic stent scaffold) and/or deliverydevices (particularly the delivery balloon) can be used to monitor theinteraction between the device(s) and surrounding tissues. This can helpprevent procedural complications such as damage to the wall of the aortaor myocardium (and/or perforation of these tissues), monitor for correctinflation and full deflation of the balloon catheter (if present), andfull deployment of the stent scaffold across the native valve. Afterdeployment, movement of the implanted valve can indicate migration ofthe device away (upstream or downstream) from its original placementsite. ISM accelerometers can also be utilized to monitor valve functionafter implantation. For example, gaps in the valve leaflets (when in theclosed position) are suggestive of leakage and regurgitation. ISMaccelerometers can also be utilized to ‘image’ valvular motion (opening,closing, and integrity of the seal), and to image changes that mightoccur over time. ISM accelerometers can detect changes in the stentscaffold: increases in diameter are indicative of possibleoverexpansion, breakage or failure; whereas decreases in the diametercan indicate possible underexpansion, collapse, breakage, or failure.

Within further embodiments of the invention ISMs are provided withsensors that can be utilized on the heart valve and delivery devices intandem in order to ensure proper placement and deployment of the heartvalve (see FIGS. 33B and 34B). Utilizing for example, ISMs having one ormore position sensors, accelerometers, and/or contact sensors, aphysician can help to ensure: 1) accurate placement across the nativevalve; 2) imaging during placement; 3) full balloon deployment anddeflation; 4) full stent (heart valve) deployment and expansion; and 5)movement or migration during or subsequent to the procedure.

B.10.A.1.4. General Consideration Regarding Heart Valves

As briefly noted above, heart valves (e.g., mechanical, biological orpercutaneous heart valves) and their associated delivery devices(guidewires, catheters, balloon catheters, and anchoring devices ifpresent) of the present invention can have one or more ISMs having oneor more of the sensors provided herein. The ISMs can be incorporated onthe surface of (in or on), or within the heart valve or deliverydevices. Representative examples of sensors include contact sensors,strain gauge sensors, pressure sensors, fluid pressure sensors, positionsensors, accelerometers, shock sensors, rotation sensors, vibrationsensors, tilt sensors, pressure sensors, blood chemistry sensors, bloodmetabolic sensors, mechanical stress sensors and temperature sensors.Sensors can be placed at a density of greater than 1, 2, 3, 4, 5, 6, 7,8, 9, 10 or greater than 10 sensors per square centimeter or at adensity of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10sensors per cubic centimeter. Within either of these embodiments therecan be less than 50, 75, 100, or 100 sensors per square centimeter, orper cubic centimeter.

ISMs having one or more of the sensors described herein can becontinuously or intermittently monitored in order to provide analysis of‘real-world’ activity, healing, and changes in function over time, toevaluate patient activity, patient cardiac function, and to betterunderstand the conditions under which artificial heart valves areexposed to in the real world. They can be utilized to detect, monitorand report, a wide variety of metabolic parameters, including forexample: Coagulation/Clotting parameters such as PT, PTT, clotting timeand INR; Blood Oxygen content; Blood CO₂ content; Blood pH; Bloodcholesterol; Blood lipids (HDL, LDL); Blood Glucose; Cardiac enzymes;Hepatic Enzymes; Electrolytes; Blood Cell Counts; and Kidney Functionparameters (BUN, Creatinine, etc.). They can also be utilized to detect,monitor and report measurements of cardiac output, ejection fraction andcardiac index; permit in situ hemodynamic monitoring of parameters suchas systolic and diastolic pressure, transvalvular pressure andregurgitation; and estimate parameters such systemic (or pulmonary)vascular resistance.

As will be readily evident given the disclosure provided herein, theISMs described and claimed herein can comprise a variety of differentsensors within different locations of the ISM. In addition, withinvarious embodiments of the invention one or more sensors may be placedseparate from the ISM (but still be, optionally, able to communicatewith and be controlled by the ISM). Representative examples of ISMs foruse with heart valves are provided in U.S. Provisional No. 62/017,161,which is hereby incorporated by reference in its entirety).

B.11. Methods of Manufacture

Within various embodiments of the invention, methods are also providedfor manufacturing a medical device having one of the sensor or ISMsprovided herein. For example, within one embodiment of the invention amedical device is constructed such that one or more sensor or ISMsprovided herein are placed directly into, onto, or within the medicaldevice at the time of manufacture, and subsequently sterilized in amanner suitable for use in subjects.

Within other embodiments, scaffolds can be prepared for medical devices(see, e.g., U.S. Pat. No. 8,562,671, and WO 2013/142879 which areincorporated by reference in their entirety). Briefly, scaffoldscomposed of one or more polymers can be prepared in order to mimic theshape of a biological structure (e.g., vessel), or a portion thereof.Sensors or ISMs can be placed into the structure before, during, orsubsequent to manufacture of the valve (e.g., in the case orelectro-spinning or molding of polymer fibers, or in the case of 3Dprinting as described in more detail below). Within certain preferredembodiments the scaffold can be seeded with stem cells suitable forgrowth of tissue on the artificial medical device (see, e.g., WO1999/003973 and U.S. Pat. No. 8,852,571, which are incorporated byreference in their entirety).

Within further embodiments, the present disclosure provides a method ofmaking a medical device by 3D printing, additive manufacturing, or asimilar process whereby the medical device is formed from powder orfilament that is converted to a fluid form such subsequently solidifiesas the desired shape. For convenience, such processes will be referredto herein as printing processes or 3D printing processes. The presentdisclosure provides a method of making a medical device by a printingprocess, where that medical device includes a sensor or ISM. The sensoror ISM may be separately produced and then incorporated into the medicaldevice during the printing process. For example, a sensor or ISM may beplaced into a desired position and the printing process is carried outaround the sensor or ISM so that the sensor or ISM becomes embedded inthe printed medical device. Alternatively, the printing process may bestarted and then at appropriate times, the process is paused to allow asensor or ISM to be placed adjacent to the partially completed medicaldevice. The printing process is then re-started and construction of themedical device is completed. The software that directs the printingprocess may be programmed to pause at appropriate predetermined times toallow a sensor or ISM to be added to the partially printed medicaldevice.

In addition, or alternatively, the sensor or ISM itself, or a portionthereof may be printed by the 3D printing process. Likewise, electronicconnectively to, or from, or between, sensor or ISMs may be printed bythe 3D printing process. For example, conductive silver inks may bedeposited during the printing process to thereby allow conductivity to,or from, or between sensor or ISMs of a medical device. See, e.g., PCTpublication nos. WO 2014/085170; WO 2013/096664; WO 2011/126706; and WO2010/0040034 and US publication nos. US 2011/0059234; and US2010/0037731. Thus, in various embodiments, the present disclosureprovides medical devices wherein the sensor or ISM is printed onto asubstrate, or a substrate is printed and a sensor or ISM is embedded orotherwise incorporated into or onto the substrate, or both the substrateand the sensor or ISM are printed by a 3D printing technique.

3D printing may be performed using various printing materials, typicallydelivered to the 3D printer in the form of a filament. Two commonprinting materials are polylactic acid (PLA) andacrylonitrile-butadiene-styrene (ABS), each being an example of athermoplastic polymer. When strength and/or temperature resistance isparticularly desirable, then polycarbonate (PC) may be used as theprinting material. Other polymers may also be used. See, e.g., PCTpublication nos. WO 2014/081594 for a disclosure of polyamide printingmaterial. When metal parts are desired, a filament may be prepared frommetal or metal alloy, along with a carrier material which ultimatelywill be washed or burned or otherwise removed from the part after themetal or metal alloy has been delivered.

When the medical device is of a particularly intricate shape, it may beprinted with two materials. The first material is cured (using, e.g.,actinic radiation) as it is deposited, while the second material isuncured and can be washed away after the medical device has been finallyprinted. In this way, significant hollow spaces may be incorporated intothe medical device.

Additive manufacturing is a term sometimes used to encompass printingtechniques wherein metal or metal allow is the material from which thedesired part is made. Such additive manufacturing processes utilizeslasers and build an object by adding ultrathin layers of materials oneby one. For example, a computer-controlled laser may be used to directpinpoint beams of energy onto a bed of cobalt-chromium alloy powder,thereby melting the alloy in the desired area and creating a10-30-micron thick layer. Adjacent layers are sequentially andrepetitively produced to create the desired sized item. As needed, asensor or ISM may be embedded into the alloy powder bed, and the lasermelts the powder around the sensor or ISM so as to incorporate thesensor or ISM into the final product. Other alloys, including titanium,aluminum, and nickel-chromium alloys, may also be used in the additivemanufacturing process. See, e.g., PCT publication nos. WO 2014/083277;WO 2014/074947; WO 2014/071968; and WO 2014/071135; as well as USpublication nos. US 2014/077421; and US 2014/053956.

Accordingly, in one embodiment the present disclosure provides a methodof fabricating a sensor or ISM-containing medical device, the methodcomprising forming at least one of a sensor or ISM and a support for thesensor or ISM using a 3D printing technique. Optionally, the 3D printingtechnique may be an additive manufacturing technique. In a relatedembodiment, the present disclosure provides a medical device that isproduced by a process comprising a 3D printing process, such as anadditive manufacturing process, where the medical device includes asensor or ISM.

Disclosure of 3D printing processes and/or additive manufacturing isfound in, for example PCT publication nos. WO 2014/020085; WO2014/018100; WO 2013/179017; WO 2013/163585; WO 2013/155500; WO2013/152805; WO 2013/152751; WO 2013/140147 and US publication nos.2014/048970; 2014/034626; US 2013/337256; 2013/329258; US 2013/270750.

Within yet other embodiments of the invention methods of fabricating amedical device having a sensor or one or more ISMs are providedcomprising the steps of forming an implantable medical device (e.g., asdescribed herein), and implanting a sensor into the device during thefabrication process. Within further embodiments, such methods furthercomprise the steps of determining a medical device shape that issuitable for a particular subject, or a particular group of subjects(e.g., by imaging a subject, and utilizing CAD programs or other 3-Ddesign programs to design a suitable medical device for a particularsubject, or, for a group of subjects. Within yet further embodiments,one or more ISMs can be implanted onto a medical device in a particularlocation for a particular subject. For example, based upon imaging(e.g., CT, MRI, ultrasound, or other forms of analysis), stent graftscan be designed so that one or more ISMs, or components thereof (e.g.,communication modules and/or batteries) can be placed on a stent graftso that, once implanted, they would fall within an aneurysm sac of asubject.

C. Use of Medical Devices or Implants having ISMs to Deliver TherapeuticAgent(s)

As noted above, the present invention also provides drug-eluting medicaldevices or implants which comprise one or more ISMs, and which can beutilized to release a therapeutic agent (e.g., a drug) to a desiredlocation within the body (e.g., a body tissue such as bone marrow, orsites of possible or typical infection or inflammation). Within relatedembodiments, a drug-eluting delivery device may be included within themedical device in order to release a desired drug upon demand (e.g.,upon remote activation/demand, or based upon a timed schedule), or upondetection of an activating event (e.g., detection of an accelerometer ofa significant impact event, or detection of loosening by a contactsensor) (see generally U.S. Patent App. No. 2011/0092948 entitled“Remotely Activated Piezoelectric Pump For Delivery of Biological Agentsto the Intervertebral Disc and Bone”, which is incorporated by referencein its entirety).

For example, within certain embodiments of the invention, biologicalagents can be administered along with or released from an orthopedicimplant in order to increase bone growth, fibrosis or scarring withinthe implant. Representative examples of suitable agents include, forexample, irritants, silk, wool, talcum powder, metallic beryllium, andsilica. Other agents which may be released by the orthopedic implantinclude components of extracellular matrix, fibronectin, polylysine,ethylenevinylacetate, and inflammatory cytokines such as TGFβ, PDGF,VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, BMP and growthhormone, and adhesives such as cyanoacrylate (see U.S. Patent App. Nos.2005/0149173 and 2005/0021126, both of which are incorporated byreference in their entirety).

Within other embodiments of the invention anti-scarring biologicalagents (e.g., drugs such as paclitaxel, sirolimus, or an analog orderivative of these), can be administered along with or released from anorthopedic implant or a vascular implant in order to prevent scarring ofthe implant inappropriately (see, e.g., U.S. Pat. No. 7,491,188, U.S.Patent Application Nos. 2005/0152945, 2005/0187639, 2006/0079836, US2009/0254063, US 2010/0023108, and US 2010/0042121).

Within other embodiments of the invention, anti-inflammatory agents,local anesthetics and pain-relief medications (e.g., drugs such ascortisone, dexamethasone, nonsteroidal anti-inflammatories, lidocaine,bupivacaine, marcaine, morphine, codeine, narcotic pain relievers andanalogs or derivatives of these) can be utilized to reducepost-operative pain and swelling and reduce the need for systemic painrelief therapy.

Within other embodiments a wide variety of additional therapeutic agentsmay be delivered (e.g., to prevent or treat an infection such asosteomyelitis, myocarditis, biofilm formation, or to treat anotherdisease state such as a primary or secondary bone tumor), including forexample: Anthracyclines (e.g., gentamycin, tobramycin, doxorubicin andmitoxantrone); Fluoropyrimidines (e.g., 5-FU); Folic acid antagonists(e.g., methotrexate); Podophylotoxins (e.g., etoposide); Camptothecins;Hydroxyureas, and Platinum complexes (e.g., cisplatin) (see e.g., U.S.Pat. No. 8,372,420 which is incorporated by reference in its entirety.Other therapeutic agents include beta-lactam antibiotics (e.g., thepenicillins, cephalosporins, carbacephems and carbapenems);aminoglycosides (e.g., sulfonamides, quinolones and the oxazolidinones);glycopeptides (e.g., vancomycin); lincosamides (e.g., clindamycin);lipopeptides; macrolides (e.g., azithromycin); monobactams; nitrofurans;polypeptides (e.g., bacitracin); and tetracyclines.

Within preferred embodiments one or more ISMs can be utilized todetermine appropriate placement of the desired drug, as well as thequantity and release kinetics of drug to be released at a desired site.

D. Methods for Monitoring Infection in Medical Devices or Implants

Within other embodiments medical devices or implants are providedcomprising an ISM having one or more temperature sensors. Such medicaldevices or implants can be utilized to measure the temperature of themedical device, and in the local tissue adjacent to the medical device.Methods are also provided for monitoring changes in temperature overtime, in order to determine and/or provide notice (e.g., to a patient ora healthcare provider) that an infection may be imminent. For example,an ISM having temperature sensors can be included within one or morecomponents of the medical device in order to allow early detection ofinfection could allow preemptive treatment with antibiotics or surgicaldrainage and eliminate the need to surgically remove the medical device.

In certain embodiments of the present invention, ISMs having metabolicand physical sensors can also be placed on or within the variouscomponents of a device or implant in order to monitor for rare, butpotentially life-threatening complications of medical devices. In somepatients, the medical device and surrounding tissues can becomeinfected; typically from bacteria colonizing the patient's own skin thatcontaminate the surgical field or the device surface (oftenStaphylococcus aureus or Staphylococcus epidermidis). ISMs havingsensors such as temperature sensors (detecting temperature increases),pH sensors (detecting pH decreases), and other metabolic sensors (e.g.oxygen content, CO₂ content, bacterial DNA detection assays) can be usedto suggest the presence of infection on or around the medical device.

Hence, within one embodiment of the invention methods are provided fordetermining an infection associated with a medical device, comprisingthe steps of a) providing to a patient an medical device as describedherein, wherein the medical device comprises an ISM having at least onetemperature sensor and/or metabolic sensor, and b) detecting a change insaid temperature sensor and/or metabolic sensor, and thus determiningthe presence of an infection. Within various embodiments of theinvention the step of detecting may be a series of detections over time,and a change in the sensor is utilized to assess the presence ordevelopment of an infection. Within further embodiments a change of0.5%, 1.0%, or 1.5% elevation of temperature or a metabolic factor overtime (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4 hours, 12 hours, 1 day,or 2 days) can be indicative of the presence of an infection (or adeveloping infection).

Within various embodiments of the invention an antibiotic may bedelivered in order to prevent, inhibit or treat an infection subsequentto its detection. Representative examples of suitable antibiotics arewell known, and are described above under Section C (the “TherapeuticAgents”)

E. Further Uses of ISM-Containing Medical devices in Healthcare

ISM having sensors on medical devices, and any associated medical devicehave a variety of benefits in the healthcare setting, and innon-healthcare settings (e.g., at home or work). For example,postoperative progress can be monitored (readings compared fromday-to-day, week-to-week, etc.) and the information compiled and relayedto both the patient and the attending physician allowing rehabilitationto be followed sequentially and compared to expected (typicalpopulation) norms. Within certain embodiments, a wearable deviceinterrogates the ISM sensors on a selected or randomized basis, andcaptures and/or stores the collected sensor data. This data may then bedownloaded to another system or device (as described in further detailbelow).

Integrating the data collected by the ISM sensors described herein(e.g., contact sensors, position sensors, strain gauges and/oraccelerometers) with simple, widely available, commercial analyticaltechnologies such as pedometers and global positioning satellite (GPS)capability, allows further clinically important data to be collectedsuch as, but not restricted to: extent of patient ambulation (time,distance, steps, speed, cadence), patient activity levels (frequency ofactivity, duration, intensity), exercise tolerance (work, calories,power, training effect), range of motion and medical device performanceunder various “real world” conditions. It is difficult to overstate thevalue of this information in enabling better management of the patient'srecovery. An attending physician (or physiotherapist, rehabilitationspecialist) only observes the patient episodically during scheduledvisits; the degree of patient function at the exact moment ofexamination can be impacted by a multitude of disparate factors such as:the presence or absence of pain, the presence or absence ofinflammation, time of day, compliance and timing of medication use (painmedications, anti-inflammatories), recent activity, patient strength,mental status, language barriers, the nature of their doctor-patientrelationship, or even the patient's ability to accurately articulatetheir symptoms—to name just a few. Continuous monitoring and datacollection can allow the patient and the physician to monitor progressobjectively by supplying objective information about patient functionunder numerous conditions and circumstances, to evaluate how performancehas been affected by various interventions (pain control,anti-inflammatory medication, rest, etc.), and to compare patientprogress versus previous function and future expected function. Bettertherapeutic decisions and better patient compliance can be expected whenboth the doctor and the patient have the benefit of observing the impactof various treatment modalities on patient rehabilitation, activity,function and overall performance.

F. Generation of Power from Medical Devices or Implants

Within certain aspects of the invention, a small electrical generationunit can be positioned along an outer, or alternatively an inner,surface of the medical device, or associated medical device. Briefly, avariety of techniques have been described for scavenging power fromsmall mechanical movements or mechanical vibration. See, for example,the article entitled “Piezoelectric Power Scavenging of MechanicalVibration Energy,” by U.K. Singh et al., as published in the AustralianMining Technology Conference, Oct. 2-4, 2007, pp. 111-118, and thearticle entitled “Next Generation Micro-power Systems by Chandrakasan etal., as published in the 2008 Symposium on VLSI Circuits Digest ofTechnical Papers, pp. 1-5. See also U.S. Pat. No. 8,283,793 entitled“Device for Energy Harvesting within a Vessel,” and U.S. Pat. No.8,311,632 entitled “Devices, Methods and Systems for Harvesting Energyin the Body,” all of the above of which are incorporated by reference intheir entirety. These references provide examples of different types ofpower scavengers which can produce electricity from very small motionand store the electricity for later use. The above references alsodescribes embodiments in which pressure is applied and released from theparticular structure in order to produce electricity without the needfor motion, but rather as a result of the application of high pressure.In addition, these references describe embodiments wherein electricitycan be produced from pulsatile forces within the body and movementswithin the body.

After the electricity is generated by one or more generators, theelectricity can be transmitted to any one of the variety of sensorswhich is described herein. For example, it can be transmitted to any ofthe sensors shown in Figures. It may also be transmitted to the othersensors described herein. The transmission of the power can be carriedout by any acceptable technique. For example, if a ISM sensor isphysically coupled to the medical device, electric wires may run fromthe generator to the particular sensor. Alternatively, the electricitycan be transmitted wirelessly in the same way that wireless smartcardsreceive power from closely adjacent power sources using the appropriatesend and receive antennas. Such send and receive techniques of electricpower are also described in the publication and the patent applicationsand issued U.S. patent previously described, all of which areincorporated herein by reference.

G. Medical Imaging and Self-Diagnosis of Assemblies Comprising MedicalDevices or Implants; Predictive Analysis and Predictive Maintenance

Within other aspects of the invention methods are provided for imagingthe medical device as provided herein, comprising the steps of (a)detecting the location of one or more ISM sensors in the medical device,and/or associated medical device; and (b) visually displaying thelocation of said one or more ISM sensors, such that an image of themedical device and/or medical device is created. Within variousembodiments, the step of detecting may be done over time, and the visualdisplay may thus show positional movement over time. Within certainpreferred embodiments the image which is displayed is athree-dimensional image. Within preferred embodiments the various images(e.g., 2D or 3D) may be collected and displayed in a time-sequence(e.g., as a moving image or ‘movie-like’ image). Within otherembodiment, the imaging techniques may be utilized post-operatively inorder to examine the medical device, and/or to compare operation and/ormovement of the device over time such as during placement(intra-operatively) or during the post-operative (rehabilitative)period.

The present invention provides medical devices and associated medicaldevices which are capable of imaging through the use of ISM havingsensors over a wide variety of conditions. For example, within variousaspects of the invention methods are provided for imaging the medicaldevice (or portion thereof) having an ISM (and/or delivery device,comprising the steps of detecting the changes in the ISM in, on, and orwithin the medical device, medical device or kit over time, and whereinthe medical device, medical device or kit comprises one or more ISMhaving sensors at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9,10 or greater than 10 sensors per square centimeter. Within otheraspects the medical device medical device or kit comprises an ISM havingsensors at a density of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 orgreater than 10 sensors per cubic centimeter. Within either of theseembodiments there can be less than 50, 75, 100, or 100 sensors persquare centimeter, or per cubic centimeter. Within various embodimentsthe at least one or more of the sensors may be placed randomly, or atone or more specific locations within the medical device, medicaldevice, or kit as described herein. As noted above, a wide variety ofsensors can be utilized therein, including for example, contact sensors,strain gauge sensors, pressure sensors, fluid pressure sensors, positionsensors, tissue chemistry sensors, tissue metabolic sensors, mechanicalstress sensors, and temperature sensors.

For example, the medical device, medical device, or kit comprisingsensors as described herein can be utilized to image anatomy throughsensors which can detect positional movement. The sensors used can alsoinclude accelerometers and motion sensors to detect movement of themedical device due to a variety of physical changes. Changes in theposition of the accelerometers and/or motion sensors over time can beused as a measurement of changes in the position of the medical deviceover time. Such positional changes can be used as a surrogate marker ofmedical device anatomy—i.e. they can form an “image’ of the medicaldevice to provide information on the size, shape, integrity, alignmentand location of changes to the medical device, and/or medical devicemovement/migration. In particular, as noted above the image data can becollected over time, in order to visually show changes (e.g., a “movie”or ‘moving images“, which may be in 2D or 3D).

Certain exemplary embodiments will now be explained in more detail. Oneparticular benefit is the live and in-situ monitoring of the patient'srecovery with a medical device having an ISM as described herein. TheISM can, optionally, collect data on a constant basis, during normaldaily activities and even during the night if desired. For example,contact sensors within an ISM can obtain and report data once every 10seconds, once a minute, or once a day. Other sensors can collect datamore frequently, such as several times a second. For example, it wouldbe expected that the temperature, contact, and/or position data could becollected and stored several times a second. Other types of data mightonly need to be collected by the minute or by the hour. Still othersensors may collect data only when signaled by the patient to do so (viaan external signaling/triggering device) as part of “eventrecording”—i.e. when the patient experiences a particular event (e.g.pain, injury, instability, etc.)—and signals the device to obtain areading at that time in order to allow the comparison ofsubjective/symptomatic data to objective/sensor data in an effort tobetter understand the underlying cause or triggers of the patient'ssymptoms. All activity can be continuously monitored post operation orpost-procedure and the data collected and stored in the memory locatedinside the medical device.

A patient with a medical device will generally have regular medicalcheckups. When the patient goes to the doctor's office for a medicalcheckup, the doctor will bring a reading device closely adjacent to themedical device or ISM 10, in this example the medical device, in orderto transfer the data from the internal circuit inside the medical deviceto the database in the physician's office. The use of wirelesstransmission using smartcards or other techniques is very well known inthe art and need not be described in detail. Examples of such wirelesstransmission of data are provided in the published patent applicationsand patents which have been described herein. The data which has beencollected (e.g., over a short period of time, over several weeks or evenseveral months) is transferred in a few moments from the memory which ispositioned in the medical device to the doctor's computer or wirelessdevice. The computer therefore analyzes the data for anomalies,unexpected changes over time, positive or negative trends, and othersigns which may be indicative of the health of the patient and theoperability of the medical device. For example, if the patient hasdecided to go skiing or jogging, the doctor will be able to monitor theeffect of such activity on the medical device having an ISM, includingthe accelerations and strains during the event itself. The doctor canthen look at the health of the medical device in the hours and daysafter the event and compare it to data prior to the event to determineif any particular event caused long term damage, or if the activitiessubjected the medical device to forces beyond the manufacturer'sperformance specifications for that particular medical device. Data canbe collected and compared with respect to the ongoing and long termperformance of the medical device from the strain gauges, the contactsensors, the surface wear sensors, or other sensors which may bepresent. Hence, within preferred embodiments the data can be collectedover time, in order to visually show changes (e.g., a 2D or 3D “movie”or ‘moving images”).

In one alternative, the patient may also have such a reading device intheir home which collates the data from the medical device on a periodicbasis, such as once per day or once per week. As described above, thepatient may also be able to “trigger” a device reading (via an externalsignaling/triggering device) as part of “event recording.” Empoweringthe patient to follow their own rehabilitation—and enabling them to seethe positive (and negative) effects of various lifestyle choices ontheir health and rehabilitation—can be expected to improve complianceand improve patient outcomes. Furthermore, their experience can beshared via the web with other patients to compare their progress versusexpected “norms” for function and rehabilitation and alert them to signsand symptoms that should be brought to their doctor's attention. Theperformance of different medical devices can be compared in differentpatients (different sexes, weights, activity levels, etc.) to helpmanufacturers design better devices and assist surgeons and otherhealthcare providers in the selection of the right medical device forspecific patient types. Payers, patients, manufacturers and physicianscould all benefit from the collection of this comparative information.Lastly, data accumulated at home can be collected and transmitted viathe Internet to the physician's office for analysis—potentiallyeliminating unnecessary visits in some cases and encouraging immediatemedical follow-up in others.

H. Methods of Monitoring Assemblies Comprising Medical Devices with ISMs

As noted above, the present invention also provides methods formonitoring one or more of the medical devices or implants with ISMsprovided herein. For example, FIG. 35 illustrates a monitoring systemusable with the medical device or ISM 10 as of the type shown in any oneof the Figures described herein.

Within other embodiments, the monitoring system however may be composedof passive sensors, which respond to an external signal. For example,according to one embodiment, sufficient signal strength is provided inthe initial signal to provide power for the sensor and to carry out thesensing operation and output the signal back to an interrogation module.In other embodiments, two or more signals are sent, each signalproviding additional power to the sensor to permit it to complete thesensing operation and then provide sufficient power to transfer the datavia the signal path back to the interrogation module. For example, thesignal can be sent continuously, with a sensing request component at thefirst part of the signal and then continued providing, either as asteady signal or pulses to provide power to operate the sensor. When thesensor is ready to output the data, it sends a signal alerting theinterrogation module that data is coming and the signal can be turnedoff to avoid interference. Alternatively, the integration signal can beat a first frequency and the output signal at a second frequencyseparated sufficiently that they do not interfere with each other. In apreferred embodiment, they are both the same frequency so that the sameantenna on the sensor can receive the signal and send signal.

The interrogation signal may contain data to select specific sensors onthe medical device. For example, the signal may power up all sensors onthe medical device at the same time and then send requests for data fromeach at different selected times so that with one interrogation signalprovided for a set time, such as 1-2 seconds, results in each of thesensors on the medical device collecting data during this time periodand then, at the end of the period, reporting the data out on respectivesignals at different times over the next 0.5 to 2 seconds so that withone interrogation signal, the data from all sensors is collected.

While the wireless signal can be in any frequency range, within certainembodiments an RF range is preferred. A frequency in the VLF to LFranges of between 3-1300 kHz is preferred to permit the signal to becarried to sufficient depth inside the body with low power, butfrequencies below 3 kHz and above 1300 kHz can also be used. The sensingdoes not require a transfer of large amounts of data and low power ispreferred; therefore, a low frequency RF signal is acceptable. This alsoavoids competition from and inadvertent activation by other wirelesssignal generators, such as blue tooth, cell phones and the like.

The interrogation module is operating under control of the control unitwhich has a microprocessor for the controller, a memory, an I/O circuitto interface with the interrogation module and a power supply. Thecontrol unit may output data to a computer or other device for displayand use by the physician to treat the subject.

I. Collection, Transmission, Analysis, and Distribution of Data fromAssemblies Comprising Medical Devices or Implants

FIG. 35 illustrates one embodiment of an information and communicationtechnology (ICT) system 800 arranged to process sensor data (e.g., datafrom the ISM 10). In FIG. 35, the ICT system 800 is illustrated toinclude computing devices that communicate via a network 804, however inother embodiments, the computing devices can communicate directly witheach other or through other intervening devices, and in some cases, thecomputing devices do not communicate at all. The computing devices ofFIG. 35 include computing servers 802, and other devices that are notshown for simplicity.

In FIG. 35, one or more ISMs 10 communicate with a remote data receivingdevice 82. The remote data receiving device can be a wearable device(e.g., a watch-like device, a wrist-band, or other device that may becarried or worn by the subject) can interrogate the ISMs over a set (orrandom) period of time, collect the data, and forward the data on to oneor more networks (804). Alternatively, the remote data receiving device82 can be a stationary device in a hospital, home, or office. The remotedata receiving device 82 may collect data of its own accord which canalso be transmitted to the network. Representative examples of data thatmay be collected include location (e.g., a GPS), body or skintemperature, and other physiologic data (e.g., pulse). Within yet otherembodiments, the remote data receiving device may notify the subjectdirectly of any of a number of prescribed conditions, including but notlimited to possible or actual failure of the device.

The information that is communicated between the ISM 10 and the datareceiving device 82 may be useful for many purposes as described herein.In some cases, for example, sensor data information is collected andanalyzed expressly for the health of an individual subject. In othercases, sensor data is collected and transmitted to another computingdevice to be aggregated with other data (for example, the ISM data maybe collected and aggregated with other data collected from an additionaldata receiving device (e.g., a device that may, in certain embodiments,include GPS data and the like).

FIG. 35 illustrates aspects of a computing server 802 as a cooperativebank of servers further including computing servers 802 a, 802 b, andone or more other servers 802 n. It is understood that computing server802 may include any number of computing servers that operateindividually or collectively to the benefit of users of the computingservers.

In some embodiments, the computing servers 802 are arranged as cloudcomputing devices created in one or more geographic locations, such asthe United States and Canada. The cloud computing devices may be createdas MICROSOFT AZURE cloud computing devices or as some other virtuallyaccessible remote computing service.

The network 804 includes some or all of cellular communication networks,conventional cable networks, satellite networks, fiber-optic networks,and the like configured as one or more local area networks, wide areanetworks, personal area networks, and any other type of computingnetwork. In a preferred embodiment, the network 804 includes anycommunication hardware and software that cooperatively works to permitusers of computing devices to view and interact with other computingdevices.

Computing server 802 includes a central processing unit (CPU) digitalsignal processing unit (DSP) 808, communication modules 810,Input/Output (I/O) modules 812, and storage module 814. The componentsof computing server 802 are cooperatively coupled by one or more buses816 that facilitate transmission and control of information in andthrough computing server 802. Communication modules 810 are configurableto pass information between the computer server 802 and other computingdevices (e.g., computing servers 802 a, 802 b, 802 n, and the like). I/Omodules 812 are configurable to accept input from devices such askeyboards, computer mice, trackballs, and the like. I/O modules 812 areconfigurable to provide output to devices such as displays, recorders,LEDs, audio devices, and the like.

Storage module 814 may include one or more types of storage media. Forexample, storage module 814 of FIG. 35 includes random access memory(RAM) 818, read only memory (ROM) 810, disk based memory 822, opticalbased memory 8124, and other types of memory storage media 8126. In someembodiments one or more memory devices of the storage module 814 hasconfigured thereon one or more database structures. The databasestructures may be used to store data collected from sensors 22.

In some embodiments, the storage module 814 may further include one ormore portions of memory organized a non-transitory computer-readablemedia (CRM). The CRM is configured to store computing instructionsexecutable by a CPU 808. The computing instructions may be stored as oneor more files, and each file may include one or more computer programs.A computer program can be standalone program or part of a largercomputer program. Alternatively or in addition, each file may includedata or other computational support material for an application thatdirects the collection, analysis, processing, and/or distribution ofdata from sensors (e.g., medical device sensors). The sensor dataapplication typically executes a set of instructions stored oncomputer-readable media.

It will be appreciated that the computing servers shown in the figuresand described herein are merely illustrative and are not intended tolimit the scope of the present invention. Computing server 802 may beconnected to other devices that are not illustrated, including throughone or more networks such as the Internet or via the Web that areincorporated into network 804. More generally, a computing system ordevice (e.g., a “client” or “server”) or any part thereof may compriseany combination of hardware that can interact and perform the describedtypes of functionality, optionally when programmed or otherwiseconfigured with software, including without limitation desktop or othercomputers, database servers, network storage devices and other networkdevices, PDAs, cell phones, glasses, wrist bands, wireless phones,pagers, electronic organizers, Internet appliances, television-basedsystems (e.g., using set-top boxes and/or personal/digital videorecorders), and various other products that include appropriateinter-communication capabilities. In addition, the functionalityprovided by the illustrated system modules may in some embodiments becombined in fewer modules or distributed in additional modules.Similarly, in some embodiments the functionality of some of theillustrated modules may not be provided and/or other additionalfunctionality may be available.

In addition, while various items are illustrated as being stored inmemory or on storage while being used, these items or portions of themcan be transferred between memory and other storage devices for purposesof memory management and/or data integrity. In at least someembodiments, the illustrated modules and/or systems are softwaremodules/systems that include software instructions which, when executedby the CPU/DSP 808 or other processor, will program the processor toautomatically perform the described operations for a module/system.Alternatively, in other embodiments, some or all of the software modulesand/or systems may execute in memory on another device and communicatewith the illustrated computing system/device via inter-computercommunication.

Furthermore, in some embodiments, some or all of the modules and/orsystems may be implemented or provided in other manners, such as atleast partially in firmware and/or hardware means, including, but notlimited to, one or more application-specific integrated circuits(ASICs), standard integrated circuits, controllers (e.g., by executingappropriate instructions, and including microcontrollers and/or embeddedcontrollers), field-programmable gate arrays (FPGAs), complexprogrammable logic devices (CPLDs), and the like. Some or all of thesystems, modules, or data structures may also be stored (e.g., assoftware instructions or structured data) on a transitory ornon-transitory computer-readable storage medium 814, such as a hard disk822 or flash drive or other non-volatile storage device 8126, volatile818 or non-volatile memory 810, a network storage device, or a portablemedia article (e.g., a DVD disk, a CD disk, an optical disk, a flashmemory device, etc.) to be read by an appropriate input or output systemor via an appropriate connection. The systems, modules, and datastructures may also in some embodiments be transmitted as generated datasignals (e.g., as part of a carrier wave or other analog or digitalpropagated signal) on a variety of computer readable transmissionmediums, including wireless-based and wired/cable-based mediums. Thedata signals can take a variety of forms such as part of a single ormultiplexed analog signal, as multiple discrete digital packets orframes, as a discrete or streaming set of digital bits, or in some otherform. Such computer program products may also take other forms in otherembodiments. Accordingly, the present invention may be practiced withother computer system configurations.

In FIG. 35, sensor data from, e.g., ISM 10 is provided to computingserver 802. Generally speaking, the sensor data, represents dataretrieved from a known subject and from a known sensor. The sensor datamay possess include or be further associated with additional informationsuch as the USI, UDI, a time stamp, a location (e.g., GPS) stamp, a datestamp, and other information. The differences between various ISMs isthat some may include more or fewer data bits that associate the datawith a particular source, collection device, transmissioncharacteristic, or the like.

In some embodiments, the sensor data may comprise sensitive informationsuch as private health information associated with a specific subject.Sensitive information, for example sensor data from sensors e.g., 22,may include any information that an associated party desires to keepfrom wide or easy dissemination. Sensitive information can stand aloneor be combined with other non-sensitive information. For example, asubject's medical information is typically sensitive information. Insome cases, the storage and transmission of a subject's medicalinformation is protected by a government directive (e.g., law,regulation, etc.) such as the U.S. Health Insurance Portability andAccountability Act (HIPAA).

As discussed herein, a reference to “sensitive” information includesinformation that is entirely sensitive and information that is somecombination of sensitive and non-sensitive information. The sensitiveinformation may be represented in a data file or in some other format.As used herein, a data file that includes a subject's medicalinformation may be referred to as “sensitive information.” Otherinformation, such as employment information, financial information,identity information, and many other types of information may also beconsidered sensitive information.

A computing system can represent sensitive information with an encodingalgorithm (e.g., ASCII), a well-recognized file format (e.g., PDF), orby some other format. In a computing system, sensitive information canbe protected from wide or easy dissemination with an encryptionalgorithm.

Generally speaking, sensitive information can be stored by a computingsystem as a discrete set of data bits. The set of data bits may becalled “plaintext.” Furthermore, a computing system can use anencryption process to transform plaintext using an encryption algorithm(i.e., a cipher) into a set of data bits having a highly unreadablestate (i.e., cipher text). A computing system having knowledge of theencryption key used to create the cipher text can restore theinformation to a plaintext readable state. Accordingly, in some cases,sensitive data (e.g., sensor data 806 a, 806 b) is optionally encryptedbefore being communicated to a computing device.

In one embodiment, the operation of the information and communicationtechnology (ICT) system 800 of FIG. 35 includes one or more sensor datacomputer programs stored on a computer-readable medium. The computerprogram may optionally direct and/or receive data from one or moremedical device sensors medical devices in one or more subjects. A sensordata computer program may be executed in a computing server 802.Alternatively, or in addition, a sensor data computer program may beexecuted in a control unit 126, an interrogation unit 124.

In one embodiment, a computer program to direct the collection and useof medical device sensor data is stored on a non-transitorycomputer-readable medium in storage module 814. The computer program isconfigured to identify a subject who has a wireless medical deviceinserted in his or her body. The wireless medical device may include oneor more wireless sensors.

In some cases, the computer program identifies one subject, and in othercases, two or more subjects are identified. The subjects may each haveone or more medical devices or implants, and each medical device mayhave one or more ISMs of the type described herein.

The computer program is arranged to direct the collection of sensor datafrom the ISM containing medical device. Once the sensor data iscollected, the data may be further processed. For example, in somecases, the sensor data includes sensitive subject data, which can beremoved or disassociated with the data. The sensor data can beindividually stored (e.g., by unique sensor identification number,device number, etc.) or aggregated together with other sensor data bysensor type, time stamp, location stamp, date stamp, subject type, othersubject characteristics, or by some other means.

The following pseudo-code description is used to generally illustrateone exemplary algorithm executed by a computing server 802 and generallydescribed herein with respect to FIG. 35:

Start Open a secure socket layer (SSL) Identify a subject Communicatewith a predetermined control unit Request sensor data from the subjectvia the control unit Receive sensor data If the sensor data is encryptedTHEN decrypt the sensor data Store encrypted data in the selectedstorage locations Aggregate the sensor data with other sensor data Storeencrypted data in the selected storage locations Maintain a record ofthe storage transaction Perform post storage actions End

Those skilled in the art will recognize that it is common within the artto implement devices and/or processes and/or systems, and thereafter useengineering and/or other practices to integrate such implemented devicesand/or processes and/or systems into more comprehensive devices and/orprocesses and/or systems. That is, at least a portion of the devicesand/or processes and/or systems described herein can be integrated intoother devices and/or processes and/or systems via a reasonable amount ofexperimentation. Those having skill in the art will recognize thatexamples of such other devices and/or processes and/or systems mightinclude—as appropriate to context and application—all or part of devicesand/or processes and/or systems of (a) an air conveyance (e.g., anairplane, rocket, helicopter, etc.), (b) a ground conveyance (e.g., acar, ambulance, truck, locomotive, tank, armored personnel carrier,etc.), (c) a building (e.g., a home, hospital, warehouse, office, etc.),(d) an appliance (e.g., a refrigerator, a washing machine, a dryer,etc.), (e) a communications system (e.g., a networked system, atelephone system, a Voice over IP system, etc.), (f) a business entity(e.g., an Internet Service Provider (ISP) entity such as Comcast Cable,Qwest, Southwestern Bell, etc.), or (g) a wired/wireless services entity(e.g., AT&T, T-Mobile, Verizon.), etc.

In certain cases, use of a system or method may occur in a territoryeven if components are located outside the territory. For example, in adistributed computing context, use of a distributed computing system mayoccur in a territory even though parts of the system may be locatedoutside of the territory (e.g., relay, server, processor, signal-bearingmedium, transmitting computer, receiving computer, etc. located outsidethe territory).

A sale of a system or method may likewise occur in a territory even ifcomponents of the system or method are located and/or used outside theterritory. Further, implementation of at least part of a system forperforming a method in one territory does not preclude use of the systemin another territory.

In conclusion, medical devices utilizing a variety of ISMs can beutilized to serve a variety of critical clinical functions, such assafe, accurate and less traumatic placement and deployment of themedical device, procedural and post-operative “real time” imaging of themedical device and the surrounding anatomy, the early identification ofthe development of medical device complications (often prior to becomingevident by other medical diagnostic procedures), and the patient'soverall health status and response to treatment. Currently,post-operative (both in hospital and out-patient) evaluation of medicaldevice patients is through patient history, physical examination andmedical monitoring that is supplemented with diagnostic imaging studiesas required. However, most of the patient's recuperative period occursbetween hospital and office visits and the majority of data on dailyfunction goes uncaptured; furthermore, monitoring patient progressthrough the use of some diagnostic imaging technology can be expensive,invasive and carry its own health risks (the use of nuclear isotopes orcertain dyes, radiation exposure). It can, therefore, be very difficultto accurately measure and follow the development or worsening ofsymptoms and evaluate “real life” medical device performance,particularly as they relate to patient activity levels, exercisetolerance, and the effectiveness of rehabilitation efforts andmedications.

At present, neither the physician nor the patient has access to the typeof “real time,” continuous, objective, medical device performancemeasurements that they might otherwise like to have. Being able tomonitor in situ medical device function, integrity, anatomy andphysiology can provide the physician with valuable objective informationduring office visits; furthermore, the patient can take additionalreadings at home at various times (e.g. when experiencing pain, duringexercise, after taking medications, etc.) to provide importantcomplementary clinical information to the doctor (which can be sent tothe healthcare provider electronically even from remote locations). Fromthe perspective of the patient, being able to monitor many of these sameparameters at home allows them to take a more proactive role in theircare and recovery and provide him or her with either an early warningindicator to seek medical assistance or with reassurance.

In one alternative, the patient may have a reading device in their homewhich collates the data from the medical device on a periodic basis,such as once per day or once per week. For example, within certainembodiments the devices and systems provided herein can instruct orotherwise notify the patient, or a permitted third-party as todeviations (e.g., greater than 10%, 20%, 25%, 50%, 70%, and or 100%)from normal, and/or, set parameters. In addition to empowering thepatient to follow their own rehabilitation—and enabling them to see thepositive (and negative) effects of various lifestyle choices on theirhealth and rehabilitation—such information access can be expected toimprove compliance and improve patient outcomes. Furthermore, theirrecovery experience can be shared via the web with other patients tocompare their progress versus expected “norms” for function andrehabilitation and alert them to signs and symptoms that should bebrought to their doctor's attention. From a public health perspective,the performance of different medical devices can be compared indifferent patients (different sexes, disease severity, activity levels,concurrent diseases such as hypertension and diabetes, smoking status,obesity, etc.) to help manufacturers design better medical devices andassist physicians in the selection of the right medical device for aspecific patient types. Payers, patients, manufacturers and physicianscould all benefit from the collection of this comparative information.Poor and dangerous products could be identified and removed from themarket and objective long-term effectiveness data collected andanalyzed. Lastly, data accumulated at home can be collected andtransmitted via the Internet to the physician's office foranalysis—potentially eliminating unnecessary visits in some cases andencouraging immediate medical follow-up in others.

Conventions

In general, and unless otherwise specified, all technical and scientificterms used herein shall have the same meaning as those commonlyunderstood by one of ordinary skill in the art to which the embodimentpertains. For convenience, the meanings of selected terms are providedbelow, where these meanings are provided in order to aid in describingembodiments identified herein. Unless stated otherwise, or unlessimplicit from the context in which the term is used, the meaningsprovided below are the meanings intended for the referenced term.

Embodiment examples or feature examples specifically provided areintended to be exemplary only, that is, those examples are non-limitingon an embodiment. The term “e.g.” (latin, exempli gratia) is used hereinto refer to a non-limiting example, and effectively means “for example”.In addition, the Figures, while being understood to generally show thesubject matter being described, should not be seen as limiting. Forexample, while ISMs can be shown as a block, linear, or rectangularsymbolically, they can in practice look quite differently, and beattached differently than shown. For example, where ISMs are showndiagrammatically on stents as relatively linear objects, they can followthe struts or tynes of a stent and in practice be non-linear on thestent.

“Subjects” or “Patients” refers to an organism for which the medicaldevice can be utilized. Representative organisms include horses, cows,sheep, pigs, dogs, cats, rats and mice. Within one embodiment aparticularly preferred organisms are humans.

Singular terms shall include pluralities and plural terms shall includethe singular, unless otherwise specified or required by context. Forexample, the singular terms “a”, “an” and “the” include plural referentsunless the context clearly indicates otherwise. Similarly, the term “or”is intended to include “and” unless the context clearly indicatesotherwise.

Except in specific examples provided herein, or where otherwiseindicated, all numbers expressing quantities of a component should beunderstood as modified in all instances by the term “about”, where“about” means ±5% of the stated value, e.g., 100 refers to any valuewithin the range of 95-105.

The terms comprise, comprising and comprises are used to identifyessential features of an embodiment, where the embodiment may be, forexample, a composition, device, method or kit. The embodiment mayoptionally contain one or more additional unspecified features, and sothe term comprises may be understood to mean includes.

The following are some specific numbered embodiments of the devices,methods, systems and processes disclosed herein. These embodiments areexemplary only. It will be understood that the invention is not limitedto the embodiments set forth herein for illustration, but embraces allsuch forms thereof as come within the scope of the above disclosure.

1. A sensor module, comprising: a sensor channel; and a communicationinterface coupled to the sensor channel.

2. The sensor module of embodiment 1 wherein the sensor channel includesa sensor and a sensor channel coupled to the sensor and to thecommunication interface.

3. The sensor module of embodiments 1 or 2 wherein the sensor includesone or more of the following sensors: a global-positioning-system (GPS),accelerometer, Hall-effect, electrical, magnetic, thermal, pressure,radiation, optical, quantity-differential, capacitive, inductive, andtime.

4. The sensor module of any one of embodiments 1 to 3 wherein the sensoris a microelectromechanical sensor. (MEMS).

5. The sensor module of any one of embodiments 1 to 4 wherein saidsensor module includes one or more of the following sensors: fluidpressure sensors, fluid volume sensors, contact sensors, positionsensors, pulse pressure sensors, blood volume sensors, blood flowsensors, chemistry sensors, metabolic sensors, accelerometers,mechanical stress sensors and temperature sensors. Within preferredembodiments the sensor module includes an accelerometer, gyroscope, andoptionally, a temperature sensor.

6. The sensor module of any one of embodiments 1 to 5 wherein thecommunication interface includes a wireless interface.

7. The sensor module of any one of embodiments 1 to 6 wherein thecommunication interface is configured to communicate with another sensormodule.

8. The sensor module of any one of embodiments 1 to 7, furthercomprising a power supply coupled to the sensor channel and thecommunication interface.

9. The sensor module of any one of embodiments 1 to 8, furthercomprising a power supply coupled to the sensor and the communicationinterface and configured to harvest energy from an organism in which thesensor module is implanted. Within further embodiments the power supplyis a battery, which optionally, can power the sensor module continuouslyor intermittently. Within yet other embodiments the battery can powerthe sensor module in response to a signal.

10. The sensor module of any one of embodiments 1 to 9, furthercomprising a power supply coupled to the sensor channel and to thecommunication interface and configured to receive energy wirelessly.

11. The sensor module of any one of embodiments 1 to 10, furthercomprising a controller coupled to the sensor channel and thecommunication interface.

12. The sensor module of any one of embodiments 1 to 11, furthercomprising: an implantable housing; and wherein the sensor channel andthe communication interface are disposed within the housing. Withincertain embodiments of the invention, the sensor module is less thanless than 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.9, 0.8. 0.7,0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 cubic centimeters in size.

13. A medical device, comprising a medical device and a sensor moduleaccording to any one of embodiments 1 to 12.

14. The medical device according to embodiment 13, wherein said medicaldevice is a cardiovascular device, orthopedic device, spinal device,intrauterine device, cochlear implant, aesthetic implant, dentalimplant, medical polymer or artificial eye lense.

15. The medical device according to embodiment 14 wherein saidcardiovascular device is an implantable cardioverter defibrillator,pacemaker, stent, stent graft, bypass graft, catheter, or heart valve

16. The medical device according to embodiment 14, wherein saidorthopedic device is a cast, brace, tensor bandage, support, sling,tensor bandage, hip or knee prosthesis, orthopedic plate, bone screw,spinal cage, artificial disc, orthopedic pin, intramedullary device,K-wire, or orthopedic plate. Within one embodiment the medical device isa tibial extension on a total arthroplastic joint (e.g, total hip orknee joint).

17. The medical device according to embodiment 14, wherein said medicalpolymer is a biodegradable polymer.

18. The medical device according to embodiment 14, wherein said medicalpolymer is a non-biodegradable polymer.

19. The medical device according to embodiment 14, wherein said medicalpolymer is a polymethylmethacrylate, a methylmethacrylate—styrenecopolymer, fibrin, polyethylene glycol, carboxymethylcellulose, andpolyvinylalcohol.

20. The medical device according to any one of embodiments 13 to 19wherein said sensor module is located within said implant.

21. The medical device according to any one of embodiments 13 to 20wherein said medical device is sterile.

22. The medical device according to any one of embodiments 13 to 21,further comprising one or more passive sensors.

23. The medical device according to embodiment 22 wherein said passivesensors are selected from the group consisting of fluid pressuresensors, fluid volume sensors, contact sensors, position sensors, pulsepressure sensors, blood volume sensors, blood flow sensors, chemistrysensors, metabolic sensors, accelerometers, mechanical stress sensorsand temperature sensors.

24. A method, comprising: sensing a physical quantity; and generating arepresentation of the sensed quantity.

25. The method of embodiment 24 wherein the physical quantity relates toan organism.

26. The method of embodiment 24 wherein sensing the physical quantityincludes sensing the physical quantity from inside of an organism.

27. The method of embodiment 24, further comprising storing therepresentation of the sensed quantity.

28. The method of embodiment 24, further comprising transmittingwirelessly the representation of the sensed quantity to a device.

29. The method of embodiment 24, further comprising receiving wirelesslydata from a device.

30. The method of embodiment 24, further comprising: wherein the sensingand generating are performed by a first sensor module; and transmittingwirelessly the representation of the sensed quantity to a second sensormodule that is remote from the first sensor module.

31. The method of embodiment 24, further comprising: wherein the sensingand generating are performed by a first sensor module; and receivingwith the first sensor module data from a second sensor module that isremote from the first sensor module.

32. The method according to embodiment 30 or embodiment 31 wherein saidfirst sensor module is a sensor module according to any one ofembodiments 1 to 12.

33. A system, comprising: a sensor module including a battery; and abattery charger configured to charge the battery wirelessly.

34. The system according to embodiment 33 wherein said sensor module isa sensor module according to any one of embodiments 1 to 12.

35. A system, comprising: a first sensor module; and a second sensormodule configured to communicate with the first sensor module.

36. The system according to embodiment 35 wherein said sensor module isa sensor module according to any one of embodiments 1 to 12.

37. The system of embodiment 35 wherein at least one of the first andsecond sensor modules is configured to be attached to an organism.

38. The system of embodiment 35 wherein at least one of the first andsecond sensor modules is configured to be implanted in an organism.

39. The system of embodiment 35 wherein one of the first and secondsensor modules is configured to power the other of the first and secondsensor modules.

40. The medical device according to any one of embodiments 13 to 23wherein said sensor is a plurality of sensors which are positioned on orwithin said medical device at a density of greater than 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or 20 sensors per square centimeter.

41. The medical device according to any one of embodiments 13 to 23wherein said sensor is a plurality of sensors which are positioned on orwithin said medical device at a density of greater than 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or 20 sensors per cubic centimeter.

42. A method comprising:

obtaining data from sensors positioned at a plurality of locationsbetween, on, and/or within the medical device according to any one ofembodiments 13 to 23 of a subject;

storing the data in a memory device located on or within the medicaldevice; and

transferring the data from the memory to a location outside the medicaldevice.

43. The method according to embodiment 42 further comprising the step ofanalyzing said data.

44. A method for detecting and/or recording an event in a subject withthe medical device according to any one of embodiments 13 to 23,comprising the step of interrogating at a desired point in time theactivity of one or more sensors within the medical device, and recordingsaid activity.

45. The method according to embodiment 44 wherein the step ofinterrogating is performed by a subject which has said medical device.

46. The method according to embodiment 44 or 45 wherein said recordingis performed on a wearable device.

47. The method according to any one of embodiments 43 to 45 wherein saidrecording, or a portion thereof, is provided to a health care provider.

48. A method for imaging the medical device in the bone, comprising thesteps of

-   -   (a) detecting the location of one or more sensors in the medical        device according to any one of embodiments 13 to 23; and    -   (b) visually displaying the location of said one or more        sensors, such that an image of the medical device, or a portion        thereof, in the bone is created.

49. The method according to embodiment 48 wherein the step of detectingoccurs over time.

50. The method according to embodiment 47 or 48 wherein said visualdisplay shows changes in the positions of said sensors over time, and/orchanges in temperature of the sensors or surrounding tissue over time.

51. The method according to any one of embodiments 47 to 50 wherein saidvisual display is a three-dimensional image of said medical device inthe bone.

52. A method for inserting the medical device according to any one ofembodiments 13 to 23, comprising the steps of (a) inserting a medicaldevice according to any one of embodiments 13 to 23 into a subject; and(b) imaging the placement of said medical device according to the methodof an one of embodiments 47 to 50.

53. A method for examining the medical device according to any one ofembodiments 13 to 23 which has been previously inserted into a patient,comprising the step of imaging the medical device according to themethod of any one of embodiments 47 to 50.

54. A method of monitoring a medical device within a subject,comprising:

(a) transmitting a wireless electrical signal from a location outsidethe body to a location inside the subject's body;

(b) receiving the signal at a sensor positioned on a medical deviceaccording to any one of embodiments 13 to 23 located inside the body;

(c) powering the sensor using the received signal;

(d) sensing data at the sensor; and

(e) outputting the sensed data from the sensor to a receiving unitlocated outside of the body.

55. The method according to embodiment 54 wherein said receiving unit isa watch, wrist band, cell phone or glasses.

56. The method according to embodiments 54 or 55 wherein said receivingunit is located within a subject's residence or office.

57. The method according to embodiments any one of embodiments 54 to 56wherein said sensed data is provided to a health care provider.

58. The method according to any one of embodiments 54 to 57 wherein saidsensed data is posted to one or more websites.

59. A non-transitory computer-readable storage medium whose storedcontents configure a computing system to perform a method, the methodcomprising:

-   -   (a) identifying a subject, the identified subject having at        least one wireless medical device according to any one of        embodiments 13 to 23, each wireless medical device having one or        more wireless sensors;    -   (b) directing a wireless interrogation unit to collect sensor        data from at least one of the respective one or more wireless        sensors; and    -   (c) receiving the collected sensor data.

60. The non-transitory computer-readable storage medium of embodiment 59whose stored contents configure a computing system to perform a method,the method further comprising:

-   -   (a) identifying a plurality of subjects, each identified subject        having at least one medical device, each medical device having        one or more wireless sensors;    -   (b) directing a wireless interrogation unit associated with each        identified subject to collect sensor data from at least one of        the respective one or more wireless sensors;    -   (c) receiving the collected sensor data; and    -   (d) aggregating the collected sensor data.

61. The non-transitory computer-readable storage medium of embodiment 60whose stored contents configure a computing system to perform a method,the method further comprising:

-   -   (a) removing sensitive subject data from the collected sensor        data; and    -   (b) parsing the aggregated data according to a type of sensor.

62. The non-transitory computer-readable storage medium of embodiment 60whose stored contents configure a computing system to perform a method,wherein directing the wireless interrogation unit includes directing acontrol unit associated with the wireless interrogation unit.

63. The non-transitory computer readable storage medium according to anyone of embodiments 60 to 62, wherein said medical device is according toany one of embodiments 13 to 23.

64. The storage medium according to any one of embodiments 60 to 63wherein said collected sensor data is received on a watch, wrist band,cell phone or glasses.

65. The storage medium according to any one of embodiments 60 to 64wherein said collected sensor data is received within a subject'sresidence or office.

66. The storage medium according to any one of embodiments 60 to 65wherein said collected sensed data is provided to a health careprovider.

67. The storage medium according to any one of embodiments 60 to 66wherein said sensed data is posted to one or more websites.

68. The method according to any one of embodiments 54 to 58, or storagemedium according to any one of embodiments 60 to 67, wherein said datais analyzed.

69. The method or storage medium according to embodiment 68 wherein saiddata is plotted to enable visualization of change over time.

70. The method or storage medium according to embodiments 68 or 69wherein said data is plotted to provide a three-dimensional image.

71. A method for determining degradation of a medical device, comprisingthe steps of a) providing to a subject a medical device according to anyone of embodiments 13 to 23, and b) detecting a change in a sensor, andthus determining degradation of the medical device.

72. The method according to embodiment 71 wherein said sensor is capableof detecting one or more physiological and/or locational parameters.

73. The method according to embodiments 71 or 72 wherein said sensordetects a location within the subject.

74. The method according to any one of embodiments 71 to 73 wherein saidsensor moves from its original location, thereby indicating degradationof the medical device.

75. The method according to any one of embodiments 71 to 74 wherein thestep of detecting is a series of detections over time.

76. A method for determining an infection associated with a medicaldevice, comprising the steps of a) providing to a subject a medicaldevice according to any one of embodiments 13 to 23, wherein saidmedical device comprises at least one temperature sensor and/ormetabolic sensor, and b) detecting a change in said temperature sensorand/or metabolic sensor, and thus determining the presence of aninfection.

77. The method according to embodiment 76 wherein the step of detectingis a series of detections over time.

78. The method according to embodiments 76 or 77 wherein said change isgreater than a 1% change over the period of one hour.

79. The method according to any one of embodiments 76 to 78 wherein saidchange is a continually increasing temperature and/or metabolic activityover the course of 4 hours.

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification are incorporated herein by reference, in their entirety.Aspects of the embodiments can be modified, if necessary to employconcepts of the various patents, applications and publications toprovide yet further embodiments.

In general, in the following claims, the terms used should not beconstrued to limit the claims to the specific embodiments disclosed inthe specification and the claims, but should be construed to include allpossible embodiments along with the full scope of equivalents to whichsuch claims are entitled. Accordingly, the claims are not limited by thedisclosure.

1. A sensor module, comprising: a sensor channel; and a communicationinterface coupled to the sensor channel. 2-12. (canceled)
 13. A medicaldevice, comprising a medical device and a sensor module according toclaim
 1. 14-23. (canceled)
 24. A method, comprising: sensing a physicalquantity using the sensor module of claim 1; and generating arepresentation of the sensed quantity. 25-79. (canceled)